TW201120037A - Compounds and methods for treatment of cancer - Google Patents

Abstract

Compounds for treating, preventing or managing cancer are disclosed. Also provided are methods for using the compounds in treatment of various cancers. Also provided are methods of treatment using the compounds together with another chemotherapy, radiation therapy, hormonal therapy, biological therapy, or immunotherapy. Pharmaceutical compositions suitable for use in the methods are also disclosed.

Description

201120037. VI. Description of the Invention: [Technical Field of the Invention] Provided herein are compounds of formula I and compounds of formula II, methods of using the compounds to treat, prevent or manage cancer, and compositions comprising the same. The pharmaceutical dosages, dosages & dosages and dosages of the compounds and compositions provided herein are also provided. The present application claims priority to U.S. Provisional Application Serial No. 61/255,039, filed on Jan. 26, 2009. The disclosure of the above-referenced application is incorporated herein by reference in its entirety. [Prior Art] A variety of cancers are described in detail in the medical literature. Examples include bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, head and neck cancer, liver cancer, lung cancer (small cell and non-small cell lung cancer), melanoma, myeloma, nerve Blastoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, and blood cancer. As the general population ages, new cancers develop, and susceptible populations (for example, people infected with HIV or overexposed to sunlight) increase, the incidence of cancer continues to rise. However, there are limited options for treating cancer. For example, in the case of blood cancer, very few treatment options are effective, especially when conventional chemotherapy is ineffective and bone marrow transplantation is not available. Thus, there is a considerable need for novel compounds, compositions, and methods that can be used to treat, prevent, and manage a variety of cancers. SUMMARY OF THE INVENTION In an embodiment, a phantom compound is provided herein: 151808.doc 201120037

(R6)m I and pharmaceutically acceptable salts, solvates thereof (e.g., hydrates) and clathrates; wherein R1 is a functional group, an alkyl group, an alkyl group, an alkoxy group or a hydroxyl group; R2 and R3 Along with a nitrogen atom substituted therewith, a substituted or unsubstituted heterocyclic ring is formed, wherein when a substituent is present, the substituent is selected from one or more selected from the group consisting of an anthracene group, an amine group, an alkylamine group, Alkoxy, hydroxy, dentyl, n-alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, dentylaryl, heterocyclyl, heteroaryl, alkoxyalkyl, The Q1 group of the alkylcarbonyl group and the alkoxycarbonyl group; R4 and R5 are selected as follows: i) R4 and R5 are each an alkyl group, or 11) R4 and R5 together with the nitrogen atom substituted thereto form a substituted or unsubstituted a heterocyclic ring; wherein when a substituent is present, the substituents are selected from one or more Q2 groups selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and hydroxy; R6 is halo, alkyl , haloalkyl, alkoxy or hydroxy; R7 is hydrogen, halo, alkyl, halo, alkoxy or thiol; η is 0 to 2; m is 0 to 2; After 1 , 2 or 3 groups selected from the group consisting of halo, alkyl, amine 15I808.doc -4 - 201120037. Group, alkoxy, hydroxy and haloalkyl. In another embodiment, a compound of formula π is provided herein:

And pharmaceutically acceptable salts, solvates thereof (e.g., hydrates) and clathrates, wherein R and R are each independently hydrogen, a functional group, an alkyl group, a dental group, a hospitaloxy group or a hydroxyl group; R8 and R9 together with a nitrogen atom substituted therewith form a substituted or unsubstituted heterocyclic ring' wherein when a substituent is present, the substituents are selected from one or more selected from the group consisting of alkyl, amine, alkyl Amino, alkoxy, hydroxy, yl, dentate, cycloalkyl, aryl 'arylalkyl, alkylaryl, self-alkylaryl, heterocyclyl, heteroaryl, alkoxy a Q3 group of an alkyl group, an alkylcarbonyl group and an alkoxycarbonyl group; 1 2 R is a dentate group, an alkyl group, a haloalkyl group, an alkoxy group or a hydroxy group; R13 is a hydroxy group or an alkoxy group or NHR14, wherein R14 is an alkyl group , cycloalkyl or aryl; r is 0 to 2; and wherein Q3, as the case may be 1, 2 or 3 selected from the group consisting of halo, leucoyl, amine, alkoxy, hydroxy and _alkyl Replaced by the regiment. It also provides methods to treat, prevent and manage a variety of cancers. The methods comprise administering to a patient in need of such treatment or management a therapeutically effective amount of a compound of formula I or a hydrazine compound, or a pharmaceutically acceptable salt or solvate thereof, provided by 151, 808. doc 201120037, herein, Hydrate), clathrate, ester or prodrug. In addition, the scope of administration, dosage regimen, and pharmaceutical dosage for the use of such compounds are described. In certain embodiments, 'a compound that can be used herein and a treatment for H-Taiwan treatment, pre-treatment 5 or treatment include, but are not limited to, bladder cancer, brain cancer, breast cancer, cervical cancer, cancer, colon cancer. (including colorectal cancer), esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer (small cell and non-small cell lung cancer), lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate Cancer, kidney cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. The cancer can be relapsed or refractory or resistant to another treatment. In certain embodiments, the cancer includes hematological malignancies including, but not limited to, leukemia, lymphoma, and myeloma. A variety of leukemia forms include, but are not limited to, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia, and hairy cell leukemia. Leukemia can be relapsed or refractory or resistant to another treatment. In certain embodiments, the hematological malignancy is promyelocytic leukemia, T cell leukemia, or lymphoblastic leukemia. In certain embodiments, the compounds are useful for treating prostatic blood diseases, such as myelodysplastic syndromes. Further providing a method of treating, preventing, or managing cancer by administering to a subject a compound provided herein. The compound is more detailed in the compound of formula I or formula II based on a body surface area of from about 1 mg/m2 to 500 mg/m2, from about 1 mg/m2 to 3000^/1112 or from 1〇151808.doc -6 to 201120037. The doses described herein are described below in mg/m2 to 15 mg/m2. Other doses and doses of the drug are also used to treat cancer doses and dosing regimens. The dosage of the formula compound or compound of formula 11 can be delivered as a single dose, such as over a 5 minute duration (eg, a single bolus injection) or over time, such as a 24 hour period (eg, continuous infusion over time or over time) Fractional rapid administration) intravenous (IV) bolus. The compound can be repeatedly administered as needed according to the judgment of the physician. Until 5, the patient has a stable disease or experiences partial or complete disease regression, or until the patient experiences disease progression or unacceptable toxicity. In some embodiments, the compound can be administered to a patient using a cycling regimen or a formula II a7. Circulatory therapy involves administration of the active agent followed by a rest period and repeating this administration/rest cycle at least once. Circulatory therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of a therapy' and/or improve therapeutic efficacy. In another embodiment, the compound of formula I or compound of formula II is administered in combination with another pharmaceutical ("second active agent") or another therapy conventionally used to treat, prevent or manage cancer. The second active agent includes known small molecules, anticancer agents, antitumor agents or cytotoxic agents, as well as macromolecules (e.g., proteins and antibodies). Examples thereof are provided herein, as well as stem cells or cord blood. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, immunotherapy, blood transfusion, and combinations thereof. In some embodiments, the second active agent is selected from the group consisting of an alkylating agent, antimetabolite 15I808.doc 201120037, an aurora kinase inhibitor, an antagonist, an anti-dense, and a beta-fixing antagonist. Spindle poison, mitotic inhibitor, topoisomerase II inhibitor and toxicant, topoisomerase j inhibitor, antibiotic antibiotic, nitrosourea, inorganic ion complex, enzyme, hormone And hormone analogs, EGFR inhibitors, antibodies and antibody derivatives, IMID, HDAC inhibitors, Bcl-2 inhibitors, VEGF-stimulated tyrosine kinase inhibitors, VEGFR inhibitors, proteasome inhibitors, cyclin dependent Kinase inhibitors, aromatase inhibitors, dexamethasone and combinations thereof. Thus, in certain embodiments, combinations for treating, preventing, and managing solid tumors are provided herein. In other embodiments, combinations for treating, preventing, and managing blood cancer are provided herein. Pharmaceutical compositions, single unit dosage forms and dosing regimens comprising a phantom compound or a compound and a second or other active agent are also provided. The second active agent comprises a specific combination, or a "mix ((10) coffee)" of the drug or therapy, Or both. [Embodiment] Definitions, and other meanings Φ All technical and scientific terms used in this article ^ have: The same meaning is generally understood by the general practitioner. All references = applications, public applications and other publications are incorporated by reference in their entirety. Unless otherwise stated, when S gives the above definition, the U meaning in this part shall prevail. SNS_595" or "Wei Luoxing (·ι〇χίη)" 15I808.doc 201120037. Refers to (+)-1,4-dihydro-7-[(3,43)-3-methoxy -4-(Methylamino)-1-. The pyridyl]-4-oxothiazolyl)-l,8-acridin-3-indole acid has the following structure:

As used herein and unless otherwise indicated, the term "alkyl" refers to a saturated straight or branched hydrocarbon. In some embodiments, the alkyl group has from 1 to 1 、, from 1 to 6, or from 1 to 3 carbon atoms. Representative saturated linear alkyl substituents include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; and saturated branched alkyl substituents include isopropyl, t-butyl, iso Butyl, tert-butyl, isopentyl, 2-decylbutyl, 3-decylbutyl and the like. As used herein and unless otherwise indicated, the term "alkoxy" refers to a radical of the formula -OR wherein r is alkyl or haloalkyl. "Aryl" means a group of carbocyclic systems, including monocyclic, bicyclic, tricyclic, tetracyclic C6_C丨8 ring systems, at least one of which is aromatic. The aryl group may be fully aromatic, and examples are phenyl, naphthyl 'fluorenyl, fluorenyl, molyl, fluorenyl, and silk. The aryl group may also contain a combination of an aromatic ring and a non-aromatic ring, examples being ruthenium, osmium and iridium. 'Cycloalkylene' means a monovalent monocyclic or bicyclic hydrocarbon group having from 3 to 10 carbon atoms consisting solely of carbon and hydrogen atoms, and which is saturated and attached to the remainder of the molecule by a single bond, for example Cyclopropyl, \cyclohexyl, decahydrocaline and the like. 151808.doc 201120037 "dental", "halogen" or "halide" means F, CbBr or haloalkyl" means an alkyl group in which one or more hydrogen atoms are replaced by dentate. Means C|6 alkyl. Such groups include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, and the like. "Heterocyclyl" means a stable 3 to 15 membered aromatic or non-aromatic ring consisting of a carbon atom and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In the examples, the 'heterocyclic ring may be monocyclic, bicyclic or tricyclic or tetracyclic, which may include a fused ring or a bridged ring; and the nitrogen or sulfur atom of the heterocyclic ring t may be oxidized as appropriate; (d) shouting pure; and the heterocyclic ring may be aromatic or partially or fully saturated. The heterocyclic ring can be attached to the main structure at any heteroatom or carbon atom, resulting in a stable compound. Exemplary heterocyclic groups include, but are not limited to, the oxime group, the ubiquinone, the piperidinyl group, the piperidyl group, the pyrrolidinyl group, and the like. "Heteroaryl" means that the heterocyclic group as defined above is aromatic. A heteroaryl group can be attached to the main structure at any heteroatom or carbon atom to produce a stable compound. Examples of such heteroaryl groups include, but are not limited to, fluorenyl, Z pyridine, pyrimidinyl and the like. "Aromatic alkyl" means a radical of the formula RaRb, wherein Ra is an alkyl group as defined above, which is substituted, for example, with an aryl group, by Rb (aryl as defined above). "Amine" or "amino" refers to a radical of the formula -NR'R" wherein R, and R" are each hydrogen. "Alkylamine" means a group of the formula _NR, R" wherein R is hydrogen or alkyl and R" is alkyl. Thus, the term alkylamine includes monoalkylamines and dihydrogenamines. I51808.doc -10· 201120037 It should be noted that if the structure of (4) is different from the designated name of the structure, the structure depicted shall prevail. In addition, if a structure or structure is not represented, for example, by a bold or dashed line, the structure or structure is considered to cover all stereoisomers thereof. As used herein and unless otherwise indicated, the term "treatment" refers to alleviating or reducing the severity of the symptoms of the disease or condition being treated (d). π肖防” includes inhibition of the symptoms of a particular disease or condition. In some embodiments, a patient with a family history of cancer is a candidate for a prophylactic regimen. Generally, the term "prevention" refers to the administration of a drug prior to the onset of symptoms, especially in patients at risk for cancer. As used herein and unless otherwise indicated, the term "administering" encompasses preventing a patient who is 罹m#, a disease or condition from recurring the disease or condition, prolonging the time to remission of the patient suffering from the disease or condition, and reducing the mortality rate of the patient. And/or maintain a reduced severity or avoid symptoms associated with the disease or condition being managed. As used herein, an "individual" is an animal, usually a mammal, including a human, such as a patient. The term "cancer" as used herein includes, but is not limited to, solid tumors and blood-borne tumors. Therefore, the term "cancer" refers specifically to solid cancers and tumors of the skin, tissues and organs, including but not limited to bladder cancer, bone cancer or blood cancer, brain cancer, breast cancer, cervical cancer, chest cancer, colon cancer, uterus. Endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lung cancer, oral cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, laryngeal cancer and uterine cancer. The term cancer 151808.doc 201120037 also refers to hematology or hematological cancers and tumors, sometimes referred to as "liquid tumors". As used herein, "hematological malignant disease" refers to a cancer that affects blood formation or the body's blood formation and the immune system (i.e., bone marrow and lymphoid tissue). Such cancers include leukemia, lymphoma (N〇n_Hodgkin's Lymphoma), Hodgkin's disease (also known as Hodgkin's Lymphoma), and myeloma. The term "leukemia" refers to a malignant neoplasm of blood forming tissue. Leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia, and hairy cell leukemia. Leukemia can be relapsed or refractory or resistant to conventional therapies. As used herein, "T-cell leukemia" refers to a disease in which certain cells of the lymphatic system, tau lymphocytes or tau cells, are malignant. Tau cells are white blood cells that normally attack virally infected cells, foreign cells, and cancer cells and produce substances that regulate immune responses. Recurrence refers to the recurrence of signs of cancer symptoms after a period of improvement. The terms "refractory" and "resistance" refer to a condition in which cancer does not respond or is resistant to another therapy. As used herein, ICw refers to the amount, concentration, or agent haze of a 50% inhibition of the maximum response in an in vitro assay (such as a biochemical or enzymatic assay) in which a particular test compound achieves a maximum response. As used herein and unless otherwise specified, the term "in therapeutically effective" and "effective amount" means that the compound is sufficient to provide therapeutic benefit in the treatment, prevention, and/or management of the disease, sufficient delay or Minimize the amount of symptoms associated with the disease, condition, or condition to be treated. The terms ", therapeutically effective amount" and "effective amount" may encompass an amount that improves the overall therapy, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. It should be recognized that different effects can be achieved when administering a therapeutically effective amount of a compound to different patients. In some cases, the amount of compound that produces a therapeutic benefit to one patient may result in little benefit to another patient, but is still considered a therapeutically effective amount. In some embodiments, the therapeutically effective amount of the active compound is determined by the US Food and Drug Administration (or another organization in another country) to be safe in treating a disease or condition in a human patient. And the amount that is effective. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salts" includes, but is not limited to, salts of acidic or basic groups which may be present in the compounds provided herein. Under certain acidic conditions, the compound can form a variety of salts with a variety of inorganic and organic acids. The acid which can be used in the preparation of a pharmaceutically acceptable salt of such basic compounds is an acid which forms a salt comprising a pharmacologically acceptable anion, including but not limited to acetate, besylate , benzoate, bicarbonate, hydrogen tartrate, bromide, calcium edetate, camphor sulfonate 'carbonate, chloride, bromide, iodide' citrate, dihydrochloride , ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, B Indole benzoate, hexylresorcinate, hydrabamine, hydroxynaphthoate, hydroxyethylate, lactate, milk 151808.doc -13· 201120037

Sodalate, malate, maleate, mandelate, strontium, methyl sulphate, muscate, naphthenate, acid salt, pantothenate, carbonate /Diphosphate, polygalactose, salicylate, stearate, succinate, sulfate, tannin, tartrate, teacate, triethyl iodide and Hydroxynamate. Under certain conditions, the compound can form a salt with a variety of pharmacologically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, and especially calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. General information on pharmaceutically acceptable salts can be found in Stahl PH and Wermuth CG, (2QQ2) Handbook of Pharmaceutical Salts: Properties wiley_VCH/VHCA Weinheim/Ziirich. As used herein and unless otherwise indicated, the term "solvate" means a solvate formed by the association of one or more solvent molecules with a compound provided herein. The term "solvate" includes hydrates (e.g., monohydrate, dihydrate, trihydrate, tetrahydrate, and the like). As used herein and unless otherwise indicated, the term "hydrate" means a compound or a salt thereof, as provided herein, further comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. The "co-administration" and "combination with" includes the simultaneous, sequential or sequential administration of two therapeutic agents (eg, a compound of formula I or a compound of formula II and another anticancer agent) without specific time constraints. Or second agent). In one embodiment, the two agents are present simultaneously in the cell or patient's body or at the same time exert their biological or therapeutic effects. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in a respective composition or unit dosage form of 151808.doc • 14-201120037. Treat, prevent, or manage any substance that has a beneficial effect. The term "supportive care agent" refers to a compound or a compound caused by the treatment of a compound of formula II. In certain embodiments, a compound of formula 1 is provided herein.

Wherein R 1 is halo or alkyl; R 2 and R 3 together with the nitrogen atom substituted therewith form a substituted or unsubstituted heterocyclic ring, wherein when a substituent is present, the substituent is selected from the group consisting of 2 Or 3 selected from alkyl, amine, alkylamino, alkoxy, hydroxy, li, decyl, cycloalkyl, aryl, arylalkyl, alkylaryl, chiral Aryl, heterocyclyl, heteroaryl, alkoxyalkyl, alkylcarbonyl and alkoxycarbonyl Q1 groups; R4 and R5 are selected as follows: i) R4 and R5 are each alkyl, ii) R4 and R5 A substituted or unsubstituted heterocyclic ring is formed together with a nitrogen atom substituted therewith; wherein when a substituent is present, the substituent is one or two groups selected from a halogen group and an alkyl group; R6 is a halogen Base or yard; R7 is hydrogen, halo or alkyl; η is 0 or 1; and 151808.doc •15- 201120037 m is 0 or 1. In some embodiments 'η is 0. In one embodiment, 〇 is 〇. In the examples, 'R7 is hydrogen. In certain embodiments, η is 〇, the jaws are 〇 and r7 is hydrogen. In certain embodiments of Formula I, R 2 and R 3 taken together with the nitrogen atom through which they are substituted form a substituted or unsubstituted heterocyclic ring wherein, when a substituent is present, the specific substituent is selected from the group consisting of 1, 2 Or 3 selected from the group consisting of an alkyl group, an amine group, an alkyl group, an alkoxy group, a thiol group, a dentate group, a self-property group, a ring-based base group, an aryl group, a aryl group, a base group, and a tooth-burning group. a aryl group, a heterocyclic group, a heteroaryl group, an alkoxyalkyl group, a pyridyl group, and a q1 group of a calcined oxycarbonyl group. In certain embodiments of the formula, the Q1 group is selected from the group consisting of decyl, ethyl, isopropyl, trifluoro*indolyl, amine, methylamino, dimethylamino, diethylamino, and Oxyl, methoxymethyl, hydroxy, phenyl, trifluoromethylphenyl, cyclohexyl, piperidinyl. Pyrrolidinyl, fluorenylcarbonyl and tert-butoxycarbonyl. In one embodiment, R4 and R5 are each a methyl group. In one embodiment, R4 and R5, together with the nitrogen atom substituted therewith, form a substituted or unsubstituted heterocyclic ring. In one embodiment, R4 and R5 together with the nitrogen atom substituted therewith form a piperidinyl ring. In certain embodiments of the formula, 'R2 and R3 together with the nitrogen atom substituted therewith form a substituted or unsubstituted 5 or 6 membered heterocyclic ring, wherein when a substituent is present, the substituents are selected From 1, 2 or 3 selected from the group consisting of alkyl, amine, alkylamino, alkoxy, thiol, dentate, functional, cyclohexyl, aryl, arylalkyl, alkyl An aryl group, a dentylaryl group, a heterocyclic group, a heteroarylalkyloxy group, a pyridyl group, and a Q1 group of a hospital oxygen base. In certain embodiments of Formula I, the 'Q1 group is selected from the group consisting of methyl, ethyl, isopropyl, and tri-151808.doc-16-201120037 fluoromethyl, amine, methylamino, dimethylamino, Diethylamino, methoxy, methoxymethyl, hydroxy, phenyl, trifluoromethylphenyl, cyclohexyl, piperidinyl, pyrrolidinyl, methylcarbonyl and tert-butoxycarbonyl. In one embodiment, R and R are each a methyl group. In one embodiment, R4 and R5, together with the nitrogen atom substituted therewith, form a substituted or unsubstituted heterocyclic ring. In one embodiment, R4 and R5 together with the nitrogen atom to which they are substituted form a benzylidene ring. In certain embodiments of formula I, R 2 and R 3 taken together with the nitrogen atom to which they are substituted form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring, wherein when a substituent is present, the substituents Is selected from the group consisting of one, two or three selected from the group consisting of alkyl, amine, alkylamine, alkoxy, hydroxy, hydryl, haloalkyl, cycloalkyl, aryl, arylalkyl, alkane a Q1 group of a aryl group, an alkylaryl group, a heterocyclic group, a heteroaryl group, an alkoxyalkyl group, an alkylcarbonyl group, and an alkoxycarbonyl group. In certain embodiments of formula I, the Q1 group is selected from the group consisting of decyl, ethyl, isopropyl, difluorodecyl, amine, methylamino, dimethylamino, diethylamino, methoxy Base, methoxyindenyl, hydroxy, phenyl, trifluoromethylphenyl, cyclohexyl, piperidinyl, pyrrolidinyl, methylcarbonyl and tert-butoxycarbonyl. In one embodiment, R4 and R5 are each a methyl group. In one embodiment, R4 and R5, together with the nitrogen atom through which they are substituted, form a substituted or unsubstituted heterocycle. In the examples, R4 and R5 together with the nitrogen atom substituted therewith form a π-base 11 base ring. In certain embodiments of formula I, the Q1 group is selected from the group consisting of decyl, ethyl, isopropyl, trifluoromethyl, amine, decyl, decylamino, diethylamino, methoxy Methoxymethyl, hydroxy, phenyl, trifluoromethylphenyl, cyclohexyl, piperidinyl, pyrrolidinyl, fluorenylcarbonyl and tert-butoxycarbonyl. In a 151808.doc • 17· 201120037 Example t, R4 and R5 are each a f-base. Name _ In the poor example Yin, R4 and R5 together with the nitrogen atom substituted by them form a heterocyclic ring with a .4 soil attack, left or unsubstituted. In one embodiment, the quaternary 4 and R5 together with the nitrogen atom to which they are hard substituted form a piperidinyl ring. In one embodiment, R4 and R5 are each a methyl group. In one embodiment, 'bR5, together with the nitrogen atom substituted therewith, forms a substituted or unsubstituted heterocyclic ring. In the example, the nitrogen atom substituted by it forms a base ring. In one embodiment, a hydrazine compound is provided herein:

And a pharmaceutically acceptable salt, solvate (eg, hydrate) or clathrate thereof; wherein R 2 and R 3 together with the nitrogen atom substituted therewith form a substituted or unsubstituted heterocyclic ring wherein The substituents are selected from 1, 2 or 3 selected from alkyl, amine, alkylamine, alkoxy, hydroxy, dentate, dentate, cycloalkyl, aryl , arylalkyl, alkylaryl, arylalkyl, heterocyclyl, heteroaryl, alkoxyalkyl, alkylcarbonyl and alkoxycarbonyl Q1 groups; R4 and R5 are selected as follows: i R4 and R5 are each an alkyl group; or ii) R4 and R5 together with the nitrogen atom to which they are substituted form an unsubstituted 151808.doc •18·201120037 heterocyclic ring. In another embodiment, the compound of formula IB is provided herein: W1)p into

W IB and its pharmaceutically acceptable salts, solvates (such as hydrates) and clathrates, p is 〇 to 3, q is 〇 or 1, and the other variables are as described herein. Description of the premises. In one embodiment, p is deuterium, (4), is deuterium; and Q is an amine group, an alkylamino group, a hydroxyl group, an alkoxy group or an alkoxyalkyl group. In the examples, the compounds of formula IC are provided herein:

And pharmaceutically acceptable salts, solvates (e.g., hydrates) and clathrates thereof, wherein R14 is hydrogen, alkyl 'dentate alkyl, aryl, arylalkyl, alkylaryl, haran Alkaryl, alkylcarbonyl, cycloalkyl, dentylaryl, heteroaryl, heterocyclyl or alkoxycarbonyl, and other such variables are as described elsewhere herein. In one embodiment, R!4 is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, phenyl, methylcarbonyl, cyclohexyl, trifluoromethylphenyl, pyridyl, pyrrolidinyl , piperidinyl or tert-butoxycarbonyl, Qi is fluorenyl 'p is 0, 1 or 2 and q is hydrazine. In another aspect, a compound of formula ID is provided herein: 151808.doc • 19- 201120037

w

ID and its pharmaceutically acceptable salts, solvates (e.g., hydrates) and clathrates, wherein the variables are as described elsewhere herein. In one embodiment, a compound of formula IE is provided herein:

U A W and its pharmaceutically acceptable salts, solvates (e.g., hydrates), clathrates, vinegar, and prodrugs' wherein the variables are as described elsewhere herein. In another embodiment, a compound of formula IF is provided herein:

W IF and pharmaceutically acceptable salts, solvates (e.g., hydrates) and clathrates thereof, wherein the variables are as described elsewhere herein. In another embodiment, a compound of formula IG is provided herein:

And octahydrate pharmaceutically acceptable salts, solvates (e.g., hydrates) and clathrates wherein P is 〇 to 3, q is 0 or oxime, and the other variables are as described elsewhere herein. In one embodiment, p is 0, 1 or 2; and Q1 is an amine group, an alkane 151808.doc • 20·201120037 amino group, a hydroxyl group, an alkoxy group or an alkoxyalkyl group; and each of R4 and R5 is methyl. In another embodiment, a compound of formula IH is provided herein:

And pharmaceutically acceptable salts, solvates thereof (e.g., hydrates) and clathrates wherein R14 is hydrogen, alkyl, aryl, aryl, arylalkyl, alkyl aryl, Alkaryl, alkylcarbonyl, cycloalkyl, dentylaryl, heteroaryl, heterocyclyl or alkoxycarbonyl; R4 and R5 are each fluorenyl; and the other variables are as described elsewhere herein. In one embodiment, rM is hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, phenyl, methylcarbonyl, cyclohexyl, trifluoromethylphenyl, 0-bite, "比嘻" A butyl group, a tether base or a third butoxycarbonyl group, Q1 is a methyl group, hydrazine is hydrazine, 1 or 2, and R4 and R5 are each a methyl group. In certain embodiments, a compound of formula II is provided herein:

Wherein R 10 and R 11 are each independently hydrogen, halo or alkyl; R and R together with the nitrogen atom to be substituted form a substituted or unsubstituted heterocyclic ring, wherein when a substituent is present, the substituents are Selected from one or more selected from the group consisting of alkyl, amine, alkylamine, alkoxy, hydroxy, functional, haloalkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, dentate Alkyl aryl 151808.doc -21 · 201120037 base, hetero-l base, heteroaryl, alkoxyalkyl, alkyl group and agglomerated base Q3 group; R is a dentate or a burn group; R is Permeate or alkoxy; and r is deuterium or 1. In certain embodiments of Formula II, R8 and R9, together with the nitrogen atom through which they are substituted, form a substituted or unsubstituted heterocyclic ring wherein, when a substituent is present, the substituents are selected from i, 2 Or 3 selected from alkyl, amine, alkylamino, alkoxy, hydroxy, dentyl, dentate, cycloalkyl, aryl, arylalkyl, alkylaryl, dentate a Q3 group of an aryl group, a heterocyclic group, a heteroaryl group, an alkoxyalkyl group, an alkylcarbonyl group, and an alkoxycarbonyl group. In one embodiment, the Q3 group is selected from the group consisting of decyl, ethyl, isopropyl, trifluoromethyl, phenyl, trifluoromethylphenyl, amine, methylamino, dimethylamino, and Ethylamino, decyloxy, methoxymethyl, hydroxy, cyclohexyl, piperidinyl, pyrrolebityl, methylcarbonyl and tert-butoxycarbonyl. In one embodiment, each of R1〇 and Rn is hydrogen. In an embodiment, r is 〇. In certain embodiments of the formula, 'R8 and R9, together with the nitrogen atom substituted therewith, form a substituted or unsubstituted 5 or 6 membered heterocyclic ring, wherein when a substituent is present, the substituents are selected from i, 2 or 3 are selected from the group consisting of alkyl, amine, alkylamino, alkoxy, thio, halo, halo, cycloalkyl, aryl, arylalkyl, alkyl a Q3 group of a base, a functional alkylaryl group, a heterocyclic group, a heteroaryl group, an alkoxyalkyl group, an alkylcarbonyl group, and an alkoxycarbonyl group. In one embodiment, the 'Q3 group is selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, phenyl, trifluoromethylphenyl, amine, methylamino, dimethylamino, and Ethylamine 151808.doc -22· 201120037 base, methoxy, methoxymethyl, hydroxy, cyclohexyl, piperidinyl, "pyrrolidinyl, methylcarbonyl and tert-butoxycarbonyl. In one embodiment, R10 and R11 are each hydrogen. In an embodiment, r is zero. In certain embodiments of Formula II, R8 and R9, together with the nitrogen atom through which they are substituted, form a ° ratio. a base group, a base group, a oxanyl group or a morphine ring, wherein when a substituent is present, the substituents are selected from one, two or three selected from the group consisting of an alkyl group, an amine group, and an alkylamine. Alkyl, alkoxy, hydroxy, dentyl, self-alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, dalkylaryl, heterocyclyl, heteroaryl, alkoxyalkane a Q3 group of a base, an alkylcarbonyl group and an alkoxycarbonyl group. In one embodiment, the Q3 group is selected from the group consisting of a decyl group, an ethyl group, an isopropyl group, a difluoromethyl group, a phenyl group, a trifluoroindolylphenyl group, an amine group, a decylamino group, a diammonium group, Diethylamino, methoxy, methoxymethyl 'hydroxy, cyclohexyl, piperidine. Pyrrolidinyl, fluorenylcarbonyl and tert-butylcarbonyl. In one embodiment, 'R and R11 are each hydrogen. In an embodiment, r is 〇. In one embodiment, the 'Q3 group is selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, phenyl, trifluoromethylphenyl, amine, decylamino, dimethylamino, and Ethylamino, methoxy, decyloxymethyl, hydroxy, cyclohexyl, piperidinyl, pyrrolidinyl, fluorenylcarbonyl and tert-butoxycarbonyl. In one embodiment, 'R and Rl1 are each hydrogen. In an embodiment, r is 〇. In one embodiment, R10 and R11 are each hydrogen. In an embodiment, I• is 〇. In one embodiment, a compound of formula IIA is provided herein:

IIA 151808.doc -23- 201120037 and its pharmaceutically acceptable salts, solvates (eg hydrates) and clathrates where A is N or CH; s is 〇, 1, 2 or 3; and q3 Is selected from the group consisting of an alkyl group, an amine group, an alkylamino group, an alkoxy group, a hydroxyl group, a dentate group, a dentate group, a cycloalkyl group, an aryl group, an arylalkyl group, an alkylaryl group, an alkylaryl group, Heterocyclyl, heteroaryl, alkoxyalkyl, alkylcarbonyl and alkoxycarbonyl" In one embodiment, a compound of formula IIB is provided herein:

And pharmaceutically acceptable salts, solvates (eg, hydrates), clathrates, esters and prodrugs thereof, wherein Q3 is selected from the group consisting of alkyl, amine, alkylamine, alkoxy, hydroxy, _ base, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, arylalkyl, heterocyclyl, heteroaryl, siloxane, alkylcarbonyl and alkane Oxycarbonyl; and s is 0, 1 or 2. In one embodiment, a compound of formula IIC is provided herein:

And pharmaceutically acceptable salts, solvates thereof (e.g., hydrates) and clathrates, wherein R15 is hydrogen, hydrazino, dentate, aryl, arylalkyl, arylaryl, halo Alkaryl, alkylcarbonyl, cycloalkyl, functional alkylaryl, heteroaryl, heterocyclyl or alkoxycarbonyl, and other such variables are as described elsewhere herein. In one embodiment, R.sup.15 is hydrogen, decyl, ethyl, isopropyl, trifluoromethyl, phenyl, methylcarbonyl, cyclohexyl, trifluoromethylbenzene 151808.doc -24-201120037, pyridine a pyrrolidinyl, piperidinyl or a third butoxycarbonyl group, Q3 is a fluorenyl group; and s is 0, 1 or 2. In one embodiment, a compound selected from Tables I, II or III is provided herein.

Table I

Structure IC5〇A549 (μΜ) ICs〇HL60 (μΜ) 丨-毛ό AA CrN”Nis AB 〇r° ό AA rN^sb Nis A ND rNx^sb HV ό AA v^, sb HV Nis AA 151808.doc - 25- 201120037

Structure IC5〇A549 (μΜ) IC5〇HL60 (μΜ) >^N^sb ' ό AA \入\=j ND ND rx^, sb GN~ό AA °S ό MeO '~1 BCC^SO 3 people MeO BC H2N-/ N nnv X=JAA rx^sb ό AC rN^sb \__V N^s AA 151808.doc 26- 201120037

Structure ICso A549 _) ICso HL60 (μΜ) x^r"b 广'N人N人〆 ^ ό B c rN^sb b. '"ό ND ND rNi?5sb La \=j AC rN〇>s, 〇Ύ° N^S 〇ND ND rN^sb ό ND ND r^sb Y° ND ND ND rN〇!rsO H〇ό AA rNdsb 〇aw AC 151808.doc 27- 201120037

Table II

Structure ICs〇A549 (μΜ) IC5〇HL60 (μΜ) 人N人N”1 /—d ό AA 广广上N工N丁1 Nis CC Cr° ό AB Γγνν:Ν〆ND ND ί ν, ',〆 Ν工Ν Ν' HV ό BC rWs·, Kenting 1 HNy n^s BB, x^rsr >« \=j AB 151808.doc 28- 201120037

Structure IC5〇A549 (μΜ) ICs〇HL60 (μΜ) 0 A \=/ ND ND Wide Artificial J 1 〇nAJ ό BB xfrsr Wide nW 夕 S As MeO CC jrfrv MeO '^==J ND ND x^Y Η2Ν< Ν人N 入/ ό AA jrfrv HO^^N Enter N ό ND ND ^ rfrv \=j ND ND '〇0 >s WCC 151808.doc 29- 201120037

Structure IC5〇 A549 (μΜ) IC5〇 HL60 (μΜ) b. '"ό ND ND X^rY 广Ν夂Ν夂Ν" A \=j ND ND V〇N^S 〇\=/ ND ND rfrsf 1 ό ND ND rfrY 广'N*^N into 'N 夕 Y° ND ND ND rW's', 丄rPQj D 1 H〇ό BB xfrsr 0 A \=JAC

Table III

Structure IC5〇 A549 (μΜ) IC5〇 HL60 (μΜ) lNxVC00H '-〇' 0 c C -30- 151808.doc 201120037

Structure IC5〇A549 (μΜ) IC5〇HL60 (μΜ) 〇/N^A^COOH >-onInV S \=JCC 0 /N^A^COOH η2ν^ν^νΛ^ N^S \=JC c 〇/ N^A^COOH Me〇^N N" NN into S \=JC c 〇/N^A^COOH ^,1X1 H〇\ ^ n ^ \=j C c 〇.N. .COOH ^N^N: XJ NNN (^入\=J cc 〇/N^A^COOH 广N人N人N" 0 A \=IBB 0 /N^A/COOH A w BC 〇/N<=A^COOH /"ΊΜ人N人N" SN^S MeO ^ CC 151808.doc -31 - 201120037

Structure IC5〇A549 (μΜ) ICs〇HL60 (μΜ) 0 /N^AxCOOH N Human SCC 1nxVc〇〇h nn 八〆La \=jcc 1nxVc〇〇h 广 N人N八〆〆 (Λ 1 \= Jcc 1nxVc〇〇h 广N人丫"ό ND ND (^N入N八〆〇r° ό CC 1nxVc〇〇h 广 N人N八〆HNJ A \=J c C 0 rNWC00H 丄N丄N" HV Nis c C /xVcooh wide N people N gossip HNy1 N people S 1 \=jc C 151808.doc -32- 201120037

Structure IC5〇A549 (μΜ) ICs〇HL60 (μΜ) 〇/N^A^COOH N person S ND ND in;xVC00H YN JN person S 1 w ND ND 1n;xVc〇〇h input\=JCC o /N ^XxC00H ό CC /xVC00H ό ND ND Greed. H boc'N~^ N^S \=JCC In Tables I, II and III, the IC5〇 of A549 and HL60 cell lines in the MTT assay is expressed as follows: Α<3 μΜ ; 3 μΜ$Β$10 μΜ ; C> 10 μΜ ; and ND = no data. Methods of Preparation The general methods for preparing compounds of Formula I or Formula II are described below and the exemplary methods are described in the Examples section. Other compounds can be prepared using similar reactions and modifications thereof 151808.doc -33- 201120037. General procedure for the preparation of compounds of formula I and compounds of formula π

Wherein R1, R2, R3, R4, R5, R6, R7, m and η are as described elsewhere herein. Process 2

Amine, acetonitrile, diisopropylethylamine, formula 11-1

p 1 3 K and r are as described elsewhere herein, wherein R8, R9, R10, R11, r12, and 0 respectively provide a compound of formula 1-1 and a compound of formula 与 with a suitable amine or salt thereof in a suitable solvent (such as The compound of the formula and the compound of the formula II can be prepared by reacting under basic conditions in acetonitrile. Any suitable test can be used in the reaction. Exemplary tests include diisopropylethylamine, triethylamine, and the like. Starting materials can be evaluated by methods described in the Examples section, routine modifications, or routine methods known to those skilled in the art. 151808.doc • 34- 201120037 Standard Physiology, Pharmacology, and Biochemistry The program can be used to assess the biological activity of a compound. Such tests include, for example, biochemical tests (such as binding tests), radioactive integration tests, and various cell-based assays. Exemplary tests include mtt cell proliferation assays in A549 (human lung adenocarcinoma epithelial cell line) and HL60 (human promyelocytic leukemia cell) cell lines. Suitable cells include cells derived from patient samples (cancerous cell lines) by cell culture and cells derived using conventional molecular biology techniques (e.g., reverse transcription virus transfection, transfection, mutation induction, etc.). In an exemplary MTT assay, approximately 1 〇〇〇, 〇〇〇 cells (eight 549 or HL6 〇) were applied to each well of a 96-well plate. The test compounds (usually 3-fold dilutions, starting at a concentration of 2 〇 or 1 〇 μΜ per test) or dosed in duplicate with DMSO control (〇 2% final concentration) were dose-titrated. The cells were treated for 72 hours (hr) or 96 hours before analysis by the sputum method. After treatment of the compound for 72 hours or 96 hours, 1 〇卟 MTT dye solution (5 mg/mL MTT dye [Sigma #M2128] aqueous solution) was added to each well and incubated at 37 C for 2 hours. After incubation, 1 ''s solution buffer (10% SDS, 0.01 N HCl aqueous solution) was added to each well and was at 37. (: The next day, the color of the plate was analyzed at 595 nm using a colorimetric reader to correct the value obtained by processing the sample relative to the control sample. The effect of the tested compound on proliferation in various cell lines. Provided in Tables I, II, and III. In a two percent of the cases, the compounds provided herein were found to have an IC5 of less than about 20 151 808.doc in the MMT squamous proliferation assay for A549 and/or HL60 cell lines. 35·201120037 μΜ. In another embodiment, it was found that the compounds provided herein have an IC5〇 of less than about 10 μΜ for the Α549 and/or HL60 cell lines in the sputum cell proliferation assay. In another example, this article was found. The compounds provided in the ΜΤΤ cell proliferation assay have IC50 of less than about 5 μΜ, 4 μΜ, 3 μΜ, 2 μΜ, 1 μΜ, 0.5 μΜ or 0.3 μΜ for the Α549 and/or HL60 cell lines. A compound of formula j or a hydrazine compound provided herein, or a pharmaceutically acceptable salt, solvate (eg, hydrate), clathrate, ester, prodrug or stereoisomer thereof, for the treatment, prevention, and/or Manage multiple cancers Examples of cancers include solid tumors and hematological cancers. Solid tumors Accordingly, the method of treating, managing or preventing cancer is provided herein, comprising administering to an individual in need of such treatment, management or prevention about 1 ^^/ a compound of formula I or a compound of formula π at a dose of about 150 mg/m2. Cancer types include, but are not limited to, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, Head and neck cancer, liver cancer, lung cancer (small cell and non-small cell lung cancer), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, sarcoma (including osteosarcoma), skin cancer ( Including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, and uterine cancer. In one embodiment, the methods encompass the treatment, prevention, or management of colon cancer, pancreatic cancer, breast cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma , liposarcoma, melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, renal cancer, sputum adenocarcinoma, small cell lung cancer or spindle cell carcinoma. 151808.doc -36 - 201120037 In the case, it is refractory. In a leukemia, the disease is recurrent. In the embodiment, the cancer is resistant to conventional therapies in the cancer embodiment. The method provided herein, the foot #, the person & ^ ^ 盍 盍 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , π m 1 匕 匕 (i_ not limited to) chronic lymphocytic leukemia, chronic myeloid leukemia, sputum sputum f-lingual squamous leukemia, acute myeloid leukemia, acute (four) blastic leukemia and hair cells leukemia. White blood disease can be relapsed or refractory or resistant to another treatment. In certain embodiments, the hematological malignancy is promyelocytic leukemia, T cell leukemia or lymphoblastic leukemia. The methods provided herein encompass the treatment of patients who have previously undergone cancer treatment but who are not responsive to standard therapies, as well as previously untreated patients. Methods of treating patients that are not related to the age of the patient are also contemplated, although some diseases or conditions are more often provided in a particular age group, and treatments have been performed to treat patients with the disease or condition as well as without surgery. The method of surgery for patients. Because a cancer patient has complex clinical manifestations and variable clinical outcomes, treatment given to the patient may vary depending on his/her prognosis. Experienced clinicians can easily determine the specific second agent, type of surgery, and type of standard therapy based on non-drugs that can be effectively used to treat individual patients with cancer, without undue experimentation. In other embodiments, the compound of Formula I or the compound of Formula π is administered in combination with another drug ("second active agent") or another therapy for the treatment, administration or prevention of cancer. The second active agent includes small molecules and macromolecules (e.g., protein 151S08.doc • 37·201120037 cytoplasm and antibody), examples of which are provided herein, as well as stem cells or cord blood. Methods or therapies that can be used in combination with a compound of Formula I or a compound of Formula π include, but are not limited to, surgery, immunotherapy, biological therapy, radiation therapy, and other non-drugs currently used to treat, prevent, or manage cancer. Therapy. A variety of dosing regimens for the compound of formula j or a compound of formula π administered alone and/or in combination therapy are discussed herein. Pharmaceutical compositions (e.g., single unit dosage forms) useful in the methods disclosed herein are also provided. A particular pharmaceutical composition comprises a compound of formula or a compound of formula π and a second active agent. Dosage and Dosing Protocol In one embodiment, a method of treating, preventing, or managing cancer provided herein comprises administering to a patient a compound of a separate formula or a combination thereof with a second active agent based on body surface area (BSA). The body surface area can be calculated, for example, using a Mosteller formula, where: BSA(m2) = [(height (cm) x weight (kg) / 36 〇〇] i4. In one embodiment, Administration of a compound of formula I or a hydrazine compound in an oral or intravenous manner in a single or divided dose of from about i to about 500 mg/m2 '1 to about 3 mg/m2, 10 mg/m2 Up to 300 mg/m2, 20 mg/m to 150 mg/m2 or i〇mg/m2 to 120 mg/m2. In certain embodiments, the dose of the compound of formula I or the compound of formula π can be administered as a single Dosing, such as an IV bolus via a 1 〇-1 5 minute duration (eg, a single fast IV injection) or over time, such as a 24-hour period (eg, continuous infusion over time or rapid dosing over time) And repeat 'by example' as needed until the patient experiences stable disease or regression or until the patient experiences disease progression or unacceptable toxicity. Determine stable disease or instability by methods known in the art. Diseases, such as assessing patient symptoms, physical examinations, and other accepted methods of assessment. In other words, stable disease with solid tumors usually means that the vertical diameter of the measurable lesion has not increased by 250/〇 or more since the last measurement. See, for example, Resp0nse Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National / Like (1) 92(3): 205-216 (2000). Stable disease or unstable disease is determined by methods known in the art, such as assessing patient symptoms, physical examination, observation using X-rays, CAT, PET or MRI Scanned imaging of tumors and other accepted assessment methods. The amount of pharmaceutical composition administered according to the methods provided herein will depend on the individual being treated, the severity of the condition or the symptoms of the condition, the mode of administration, the frequency of administration, and the judgment of the prescribing physician. In some embodiments, the frequency of administration of the compound of Formula I or Formula II is in the range of from about one dose per day to about one dose per month. In certain embodiments, the administration is once daily 'every two days'. Once, twice a week (eg, on Days, 4, 8 and 11 days), once a week, once every two weeks, every three weeks - once or every four weeks. In one embodiment, each The pharmaceutical composition provided herein is administered once. In certain embodiments, a compound of formula or a compound of formula π is administered to a patient cyclically. Cycling therapy involves administering the active agent over a period of time, followed by a period of time and repetition. This continuous administration may reduce the development of resistance to one or more therapies, avoid or reduce the side effects of a therapy, and/or improve therapeutic efficacy. 151808.doc •39- 201120037 Therefore, in a single embodiment, the compound or formula is administered weekly in a single-person or divided dose at a rest period of about 1 to about 30 days in a 3 to 6 week cycle. The compound is in another embodiment, at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks at 1 3 5 7 9 , 12, Μ, 16, 18, 20, 22, 24, 26,

The compound of formula I or formula II is administered weekly in a single or divided dose over a 29 or 30 day rest period. In some embodiments, the waiting period is 7 days. In some embodiments, the waiting period is 14 days. In some embodiments, the waiting period is 28 days. In an embodiment, the waiting period is until recovery of sufficient bone marrow. The frequency, number and length of dosing cycles can be increased or decreased. Thus, another embodiment contemplates the administration of a compound of formula I or a compound of formula I, when administered alone, in more cycles than is typically the case. Combination Therapy In the methods and compositions provided herein, the compound of formula I or the compound of formula II can be used or combined with other pharmacologically active compounds ("second active agents"). Some combinations work in a synergistic manner to treat a particular type of cancer. The compound of formula I or a compound of formula may also act to alleviate the adverse effects associated with certain second active agents, and some second active agents may be used to alleviate the adverse effects associated with a compound of formula I or a compound of formula 其他. One or more additional active agents can be used in the methods and compositions provided herein with a compound of Formula I or a compound of Formula π. Other active agents can be macromolecules (eg, antibodies or other proteins) or small molecules (eg, synthetic inorganics). , organometallic or organic molecules. Recombinant and mutant forms of GM_CSF can be prepared as described in U.S. Patent Nos. 5,391,485, 5,393,870 and 5,229,496, 151, 808, doc. The recombinant and mutant forms of G-CSF can be prepared as described in U.S. Patent Nos. 4,8, 4, 4, 999, 291, 5, 528, 823, and 5, 58, 755, each of which is incorporated herein by reference. Incorporated herein by reference. Also provided are native, naturally occurring, and recombinant proteins for use in combination with a compound of Formula I or a compound of the formula. Further encompassing mutants and derivatives of naturally occurring proteins (e.g., modified forms) that exhibit at least some pharmacological activity in vivo to produce the protein from which they are produced. Examples of mutants include, but are not limited to, proteins having one or more amino acid residues that differ from the corresponding residues in the naturally occurring form of the protein. The term "mutant" also encompasses proteins that lack a portion of the carbohydrate that is normally found in the naturally occurring form of the protein (e.g., in a non-glycosylated form). Examples of derivatives include, but are not limited to, PEGylated derivatives and fusion proteins, such as proteins formed by fusing IgGl or IgG3 with active portions of proteins or related proteins. S.L., J. Immunol. See, for example, Penichet, M.L. and Morrison,

Methods 248:91-101 (2001) 〇 Macromolecular active agents can be administered in the form of anti-cancer vaccines. For example, a vaccine for secreting or causing secretion of cytokines such as il, 2, G-CSF and GM-CSF may be used in the methods and pharmaceutical compositions provided. See, for example, Emens, L. A. et al., CWr. Mo/. 77zer. 3(1): 77-84 (2001). In certain embodiments, the second agent can be an agent that mediates cytotoxicity via the DNA-PK pathway. Examples of such agents include compounds that inhibit non-homologous end-binding repair, such as DNA_PK inhibitors. As used herein and 151808.doc -41 · 201120037, unless otherwise stated, the term "dna-pk inhibitor" means an agent that inhibits or interferes with a DNA-PK mediated signaling pathway. The activity of DNA-PK can be inhibited directly (e.g., a catalytic inhibitor of DNA-PK itself) or indirectly (e.g., an agent that interferes with the formation of active DNA-PK complexes (DNA-PK, Ku70, and Ku80)). In one embodiment, the second agent is SNS-595. Other examples include, but are not limited to, ligase IV inhibitors and apoptosis enhancing agents such as, but not limited to, caspase-9 activators, caspase-3 activators, and HSP90 inhibitors. The small molecule second agent can also be used to alleviate the adverse effects associated with the administration of a compound of formula I or a compound of formula II. However, similar to some macromolecules, many small molecules can provide a synergistic effect when combined with a compound of formula I or a compound of formula II (for example, before, after or simultaneously with a compound of the formula " or a compound of formula II". Examples of molecular second active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressants, and steroids. Examples of anticancer second agents include, but are not limited to, alkylating agents, antibiotics, and anti-metabolites. Agents (eg, folic acid analogs, guanidine analogs, adenine analogs, chlorpyrifos analogs, and substituted ureas)' platinum coordination complexes, topoisomerase II inhibitors, and radiation. It should also be understood that A compound of formula I or a compound of formula and a pharmaceutically acceptable composition comprising a compound of formula or a compound of formula II can be used in a complementary combination therapy with a second agent or medical procedure. Thus, a compound or formula of formula 1 The compound of the II and its pharmaceutically acceptable composition can be administered simultaneously with, before or after one or more other desired active agents or medical procedures. The combination of the formula (_ or (4)) m考考151808.doc •42· 201120037 Consider the compatibility of the desired treatment/silk order and the desired therapeutic effect. It should also be understood that the therapy used may achieve the same disease; effect (eg, A compound of formula I or a compound of formula π can be administered concurrently with the treatment of the same condition as the other active agent) or it can achieve different effects (eg, control of adverse effects). Non-limiting examples of such agents and procedures include surgery Surgery, radiation therapy (eg gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, proximity therapy and systemic radioisotopes), endocrine therapy, biological response modifiers (eg interferon, interleukin and tumor necrosis factor) (TNF)), high temperature and cryotherapy, agents that attenuate any adverse effects (such as antiemetics) and other approved chemotherapeutic anticancer second agents. Can be used as a second agent in combination with a compound of the formula or a compound of formula π. Examples of chemotherapeutic anticancer agents include, but are not limited to, alkylating agents (eg, nitrogen mustard, chlorambucil, cyclophosphamide, melphalan) Isocyclic phosphoniumamines, antimetabolites (eg, methotrexate), aurora kinase inhibitors (eg, SNS-3 14, AZD-1152, PHA-739358, AT-9283), guanidine antagonists, and pyrimidine antagonists ( For example, 5-fluorouracil (5-FU), gemcitabine, and spindle inhibitors (eg, vinca alkaloids such as vinblastine, vincristine, vinorelbine) a mitotic inhibitor (eg, a taxane such as Pacific • Taxus, docetaxel 'taxotere'), a topoisomerase II inhibitor or a poison (eg epipodophyllotoxin, such as Etoposide, teniposide; anthracycline, such as doxorubicin, daunorubicin 'idarubicin', topologically different Inhibitors I (such as irinotecan 151808.doc • 43- 201120037 (irinotecan), topotecan (camptothecin), antibiotic antibiotics (such as bleomycin, Mitomycin, Affi Aphidicolin; anthracenedione, such as mitoxantrone, succinyl gland (eg carmustine, lomustine), inorganic ions (eg Ming compound) Substances such as cisplatin, acetonide, oxalilate, enzymes (such as aspartate), hormones and hormone analogues (such as tamoxifen, leuprolide, flurazepam) Flutamide, megestrol, EGFR (Herl, ErbB-1) inhibitors (eg gefitinib, erlotinib, lapatinib, BMS-599626, BMS-690514, PF-00299804, XL-647, BIBW-2992, ARRY-334543), HER antibodies (eg cetuximab, panitumumab, trastuzumab) Anti-trastuzumab), CD20 antibodies (eg rituximab, ofatumumab), antibody derivatives (eg ranibizumab), IMID (eg thalidomide) (thalidomide), lenalidomide, HDAC inhibitor (eg vorinostat) Belinostat, panobinostat, ITF-2357, SNDX-275, CI-994, apicidin, depsipeptide, trapoxin, Depeudecin, SK-7068, phenyl butyrate, valproic acid, Bcl-2 inhibitors (eg oblimersen, obatoclax), VEGFR inhibitors ( For example, sorafenib, sunitinib, vatalanib, AMG-706, CP-547632, pazopanib, 151808.doc • 44- 201120037 ΑΒΤ -869, cediranib), VEGF traps (eg, aflibercept), anti-VEGF antibodies (eg, bevacizumab), proteasome inhibitors (eg, bantezo) Rice (bortezomib), cyclin-dependent kinase (cdk) inhibitors (eg SNS-032, seliciclib), aromatase inhibitors (eg anastrozole 'Western Stein ( Exemestane), letrozole, mTOR inhibitors (eg temsirolimus, rapamycin) Rapamycin), everolimus, deforolimus, Akt inhibitors (eg perifosine, GSK-690693), Src inhibitors (eg dasatinib (dasatinib) ), bosutinib (bosutinib), XL-999, AZD-0530, KX010107), DNA methyltransferase inhibitors (eg 5-azacitidine, 5-aza-2'- Deoxycytidine), cMET inhibitors (eg XL-880, ARQ-197, PF-02341066, JNJ-388, MGCD-265, SU-1 1724, PHA-665752, OA-5D5), farnesyl transferase Inhibitors (eg tipifamib, lonafamib, BMS-214662), FTS inhibitors (eg tipifarnib, lonafarnib, BMS-214662) , Raf inhibitors (sorafenib, RAF-265, XL-281, PLX-4032), MEK inhibitors (eg AZD-6244, RDEA-119, XL-518), IGF-1R antibodies (eg CP-721871) , AMG-479, IMC-A12, R1507, BIIB022), IGF-1R inhibitors (eg XL-228, OSI-906, nordihydroguareacetic acid), HGF antibodies (eg AMG-102), PI3K Inhibitor Such as PI-103, BGT-226, BEZ-235, XL-765, XL-147), HSP90 inhibitors (such as tanespimycin, 151808.doc -45- 201120037 retaspimycin, Geldanamycin derivatives, such as 17-AAG and 17-DMAG), TRAIL agonists (eg, mapatumumab, AMG-655), survivin antagonists (eg, YM) -155, LY-2181308), PARP inhibitors (eg AG-014699, BSI-201), trabectidin and dexamethasone. For more information on the development of agents for cancer therapy, see Ma WW and Adjei AA, Cd Τ '2009, 59: 111-37. Some specific anticancer agents that can be used as a second agent in combination with a compound of formula I or a compound of formula II. These include, but are not limited to, azacitidine (5-azacitidine; for example, Vidaza®); stilzomib (eg Velcade®); carboplatin (eg Xeloda®); carboplatin (eg Paraplatin®); cisplatin (eg Platinol®); cyclopamine (eg Cytoxan®, Neosar®); cytarabine (eg Cytosar®); cytarabine liposomes (eg DepoCyt®); Other formulations of cytarabine or active moiety; doxorubicin, doxorubicin hydrochloride (eg Adriamycin®), liposomal doxorubicin hydrochloride (eg Doxil®); fludarabine; Fludarara®; 5- It urinary bite (eg Adrucil®); gefitinib (eg

Iressa®); gemcitabine hydrochloride (eg Gemzar®); irinotecan (cpt_11, camptothecin-11), irinotecan hydrochloride (eg Camptosar®); lenalidomide (eg Revlimid®); melphalan ( For example, Alkeran®); paclitaxel (such as Taxol®); protein-bound paclitaxel (for example)

Abraxane®); rituximab (eg Rituxan®); vorinostat (eg Zolinza®). It can be used as a second agent in combination with a compound of formula I or a compound of formula II. 151808.doc -46- 201120037. His anticancer agents include, but are not limited to, α5β 1 antibodies, such as volociximab; ανβ3 Anti-agents, such as vitaxin and cilengitide; acivicin; aclarubicin; acodazole hydrochloride; acronin (acronine); adalimumab (eg Humira®); adozelesin; alitretinoin (eg Panretin®); altretamine (six melamine) For example, Hexalen®); ambomycin; ametantrone acetate; aminoglutethimide (eg Cytadren®); amonafide malate (eg Xanafide®) ); amsacrine; anastrozole (eg Arimidex®); anthramycin; aspartate (eg Kidrolase®, Elspar®); asperlin ; azetepa; azotomycin; bamastat Batimastat; benzodepa; bevacizumab (eg Avastin®); bexarotene (eg Targetin®); bicalutamide (eg Cadexx®) Bisantirene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate (eg Blenoxane®); (brequinar sodium); bropirimine; busulfan (eg Busulfex®, Myleran®); CD23 antibody, such as lumisiximab; CD52 antibody such as abumab (&161111; 11211111313) (eg 〇 & 111 卩 &1;11@); 〇80 antibody' such as galiximab; cactinomycin; 151808.doc • 47- 201120037 dimethyl ketone (calusterone); caracetamide (caracemide); carbidol (carbetimer) Carmustine (eg BiCNU®); carmustine implant (eg Gliadel® powder); carubicin hydrochloride; carzelesin; sildenafil Cedefoxiol; celecoxib (COX-2 inhibitors such as Celebrex®); chlorambucil (eg Leukeran®); cirolemycin; cladribine ( For example, Leustatin®); clofarabine; cloretazine; cristatol; clinidine sulphate; 4-argonoxycyclomethamine; dacarbazine ( Dacarbazine) (eg DTIC-Dome®); dactinomycin (eg Cosmegen®); dastananib (eg Sprycel®); daunorubicin hydrochloride (eg Cerubidine®); Liposomal citrate doxorubicin (eg DaunoXome®); decitabine (5-aza-2'- Oxycytidine; for example, Dacogen®); denileukin diftitox (eg Ontak®); dexormaplatin; dezaguanine; Dizixifen; Droloxifene; Diloxifen citrate; dromostanolone propionate; duazomycin; edatrexate; Edrecolomab (Panorex®); eflornithine; efloxacin hydrochloride; elsamitrucin; enloplatin; enpromate ); epipropidine; epirubicin hydrochloride (eg Ellence®); erbulozole; erlotinib (eg Tarceva®); HCl 151808 .doc -48- 201120037 esorubicin hydrochloride; estramustine; estramustine acid (eg Emcyt®); estramustine analogue; etanidazole ; relying on etoposide (VP-16; for example Toposar®); citrate relieving (eg Etopophos®); Etoprine; hydrochloric acid method ([& (11: 〇2〇16 hydrochloride); fazarabine; fenretinide; floururidine (such as FUDR) ®); fluocitine (flurocitabine), flutamide (eg Eulexin®); fosquidone; fostriecin; fisostatin sodium; G250 monoclonal antibody; Galaximab; gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex®); hydroxyurea (eg Droxia®, Hydrea®); Ibritumomab tiuxetan (eg Zevalin®) + 丨uIn or 9° Yt; idarubicin; idamycin hydrochloride (eg Idamycin®); heterocyclic guanamine (eg eg Ifex®); immolosin; iproplatin; lanreotide; lanreotide acetate; lapatinib (eg Tykerb®); (letrozole) (eg Femara®); leuprolide acetate (eg Eligard®, Viadur®); liloro® (liarozole); hydrochloric acid lira 33; CD33 antibody, such as lintuzumab; lometrexol; lomexosone; lovastatin; butyl (eg CeeNu®); losoxantrone; Loxodonone hydrochloride; masoprocol; maytansine; mechlorethamine (nitrogen mustard, mustard), hydrochloric acid mustard (example) • 49- 151808.doc 201120037 Such as Mustargen®); megestrol acetate (eg Megace®); melengestrol acetate; menogaril; mercaptopurine (eg Purinethol) ®); amidoxime 0 such as Rheumatrex®; metoprine; meturedepa; mimitomoide; mitocarcin; lycopene Mitocromin); mitogillin; mitomalcin; mitomycin®; mitomycin analogue; mitomycin; Mittan (m.itoxantrone); mitoxantrone hydrochloride (eg Novantrone®); mycopheno Lic acid); nelarabine (Arranon®); ° serotonin nocodazole; nogalamycin; oma in white (ormaplatin); sub- 醯 <» than bite ( Oxisuran); panitumumab (eg Vectibix®); pegaspargase (PEG-L-aspartate; for example, Oncaspar®); peliomycin; pemetrex Pemetrexed (eg Alimta®); pentamustine; peplomycin sulfate; perfosfamide; pertuzumab (eg Omnitarg®); Pipobroman; 0 piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; σBumbum sodium Porfimer sodium); porfiromycin; prednimustine; procarbazine hydrochloride (eg, Matulane®); puromycin; puromycin hydrochloride; ratio. Sitting on the pyrazofurin; R-roscovitine (Selly 151808.doc -50-201120037 seliciclib); riboprine; Safingo ( Safingol); safingo hydrochloride; semustine; simtrazene; sorafenib (eg Nexavar®); sparfosate sodium; sparsomycin; Spirogermanium hydrochloride; spiromustine; spiroplati.n, streptonigrin; streptozocin (eg Zanosar®); Sulofenur; sunitinib malate (eg Sutent®); talisomycin; tecogalan sodium; tegafur; teloxime hydrochloride Teroxirone hydrochloride; temoporfin; temo. Ethylolmide (eg Temodar®); teniposide (eg Vumon®); teroxirone; testolactone; thalidomide (eg Thalomid®); sulphur Thiamiprine; thioguanidine; 6-thioguanine; °thiotepa (eg, Thioplex®); sold. Sitting on tilazofurin; tipifarnib (eg Zarnestra®); tirapazamine; topotecan (eg Hycamtin®); toremifene; Toremifene citrate (eg Fareston®); tositumomab + 1311 (eg Bexxar®); trastuzumab (eg Herceptin®); trastolone acetate ; triciribine; trimethoprim; trimetrexate; triterpene gluconate; triptorelin; troxacitabine (eg,Troxatyl®); Cloth chlorine. Sit (tubulozole hydrochloride); urine 0^ 定气芥151808.doc -51 - 201120037 (uracil mustard); uredepa (uredepa); vapreotide; verteporfin (verteporfin); vinblastine sulfate ( For example, Velban®); Changchun sulfuric acid new test (such as Vincasar®); vindesine; vindesine sulfate; vincent sulfate vinepidine sulfate; vinglycinate sulfate; vinorelbine sulfate (vinl euro sine sulfate); vinoreibine tartrate (eg, Navelbine®); vinrosidine sulfate; vinzolidine sulfate; vorozole; Zeniplatin); zinostatin; zinostatin stimalamer; and z〇rubicin (rubidazone) Other anticancer agents for use in combination with a compound of Formula I or a compound of Formula II include, but are not limited to, 20-Table-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone acetate; Acylfulvene;醯 芙 ;; adenocyclopentanol (adecypenol); ALL-TK antagonist; ambastamustine; amidox; amifostine; amino acetopropionic acid (amidostine) Aminolevulinic acid); amrubicin anagrelide (eg Agrylin®); andrographolide; angiogenesis inhibitor; antagonist d; antagonist G; antarelix Anti-dorsal morphology morphine protein-1; anti-androgen, prostate cancer; anti-estrogen; anti-nepranoplaston; antisense oligodeoxynucleotide; aphidicolin glycinate Apoptotic gene regulator; apoptosis regulator; citrate-like; ara-CDP-DL-PTBA; arginine deaminase; 131808.doc -52- 201120037 arsenic trioxide ( For example, Trisenox®; asalacrine; atamestane; atrimustine; axinsta; axin (axinstatin 1); axinsta; Axinsta; Ding 3; Azasitetron; Azatoxin; Azatyrosine; Bacillus gibberellin a derivative of III; balanol; a BCR/ABL antagonist; benzochlorin; benzamidine-based serotonin (匕6112〇71313111*〇3卩〇14116); 0 indoleamine derivative; 0-beta-alethine; β-claclamycin B; betulinic acid; bFGF inhibitor; blunt group; Bisaziridinylspermine); bisnafide; bistratene A; brefeldin A or its prodrug, breflate; budotitane ; buthionine sulfoximine; calcipotriol; calphostin C; chlorhexidine derivative (eg irinotecan); methotrexate-amine- Triazole; Carboxylamido-triazole; CaRest M3; CARN 700; cartilage-derived inhibitor; casein kinase inhibitor; castanospermine; bactericidal B (cecropin B); cetrorelix ; chlorin; 喧 喧 若 若 若 若 若 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; cis cis cis cis cis cis cis cis Cin) (eg Biaxin®); clomifene analogues; clotrimazole; collismycin A; clopidogrel B; cobant^fA4 (combretastatin A4); He, butyl analog; conagenin; crambs din 816; cryptophycin 8; krettoxin A derivative; library 151808.doc -53- 201120037 Chua A (curacin A); cyclopentamidine; cyci〇piatain; cypemycin; cytolysis factor; cytostatin; daclixos (dacliximab) (daclizumab; eg Zenapax®); dehydrodidemnin B; deslorelin; dexamethasone (eg) Decadron®; right heterocyclic filling Dexifosfamide; dexrazoxane; dexverapamil; didemnin B; didox; diethylnorspermine; dihydrogen -5-azacytidine; 9-dihydropaclitaxel; dioxamycin; diphenyl; docetaxel (eg Taxotere®); Diol; deoxyfluorouridine; doocarmycin SA; ebselen: ecomustine; edelfosine; edrecolomab ; lemmene (elemene); B. Emitefur; epristeride; estrogen agonist; estrogen antagonist; exemestane (eg Aromasin®); Sitting; filgrastim; finasteride; flavopiridol (alvocidib); said flezelastine; fluasterone ; fluorodaunorunicin hydrochloride; forfenimex; formestane; fotemustine; gadolinium texaphyrin; gallium gluconate; Galocitabine; ganciclovir; ganirelix; gelatinase inhibitor; glutathione inhibitor; Hepfarm lS1808.doc - 54- 201120037 (hepsulfam); heregulin; hexamethylene sulfonamide; hypericin; ibandronic acid; idoxifene; Idramant〇ne; ilomastat; imatinib; imatinib sulfonate (eg Gleevec®); imiquimod (eg Aldara®), and Other cytokine inducers; immunostimulatory peptides; insulin-like growth factor-1 receptor Interferon agonist; interferon, such as interferon alpha (eg Intron® A); pegylated interferon ct-2b (eg Peglntron®); interleukins such as IL-2 Aldesleukin, such as Proleukin®; IL-10, IL-12 and IL-18; ibbenguane; iododoxorubicin; 4-ipomeanol; Iroplact; irs〇giadine; isobengazole; isohomohalicondrin B; jasplakinolide; kahalalide F); lamellarin-N triacetate; leinamycin; lenograstim; ientinail sulfate; leptolstatin; leukemia Inhibitory factor; leukocyte alpha interferon; pirarillin + estrogen + progesterone; leuprorelin; levainisole; linear polyamine analog; lipophilic disaccharide peptide; lipophilic Platinum compound; lissoclinamide 7; lobaplatin; lombricine; gas nidamine (lo Nidamine); loxophone (lutotecan); iutetiUm texaphyrin; lysofylline; lytic peptide; maitansine; 151808.doc •55- 201120037 mannostatin A; marimastat; maspin; matrilysin inhibitor; matrix metalloproteinase inhibitor; mepacin (merbarone); meterelin; methioninase; metocl opr amide; MIF inhibitor; mifepristone (eg Mifeprex®); milford New (miltefosine); mirimostim; mitoguazone; mitolactol; mitonafide; mitoxantrone fibroblast growth factor-saperin ( Mitotoxin fibroblast growth factor-saporin); mofarotene; cetuximab (eg Erbitux®); human chorionic gonadotropin; monophosphoryl lipid A+ mycobacterial cell wall sk; (mopidamol); fennel anticancer agent; Indian Ocean sponge B (mycaperoxide B); Mycobacterium cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzoguanamine; nafarelin; nagrestip; Naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemomycin; Nemorubicin); neridronic acid; nilutamide (eg Nilandron®); nisamycin; nitric oxide regulator; basal oxygen antioxidant (eg tamol) )); nitrullyn; oblimersen (Genasense®); 06-phenylhydrazine guanine; octreotide (eg Sandostatin®); octreotide acetate (eg Sandostatin LAR®); Okeketone (okicenone); oligo 131808.doc -56- 201120037 nucleoside acid; onnapristone (orapristone); oracin; osaterone; oxaliplatin (eg Eloxatin®) ; oxaunomycin; paclitaxel analogue; paclitaxel derivative; balaamine Ne); palmitomycin (palmitoylrhizoxin); panaxytriol; panomifene; parabactin; pazelliptine; peldesine ); polypentose sodium polysulfate; pentostatin (eg Nipent®); pentozole; perflubron; perillyl alcohol; phenazine Phenazinomycin); phenylacetate; acidase inhibitor; picibanil; pilocarpine hydrochloride; 0 pirarubicin; 0 piritrexim; Placetin A; placetin B; plasminogen activator inhibitor; platinum-triamine complex; propyl bis-acridone; prostaglandin J2; proteasome inhibitor Protein A-based immunomodulators; protein kinase C inhibitors, including microalgae PKC inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin ;pyrazoloacridine; 0 to 0 polyacidified hemoglobin polyoxyethylene knot Pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed (eg Tomudex®); ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; Retelliptine demethylated; 铢 (Rel86); rhizoxin; ribozyme; RII retinamide; Roche 151808.doc -57- 201120037 (rohitukine); Romoted (r()rnurtide); roquinimex; rubiginone Bl; ruboxyl; saintopin, SarCNU; sarcophytol A Sdi 1 mimetic; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor, sizofiran; sobuzuxane; which [10B] sodium borocaptate Sodium phenylacetate; solverol, growth-promoting factor binding protein; s〇nerinin; sparfosic acid; spicamycin D; spleen pentapeptide Splenopentin); sponstatin i (sp〇ngistatin 1); squalamine 'steroids' (eg Prednisone (pre (ninis), prednisolone); stipiamide; stromelysin inhibitor; sulfinosine; sulindac Superactive catalin antagonist; suradista, suramin; swainsonine; tallimustine; tamoxifen; citric acid Moxifen (for example

Nolvadex ), tam〇xifen methiodide; tauromustine; tazarotene; tellurapyrylium, telomere Enzyme inhibitor (tei〇nierase inhibitor); four gas decaoxide, tetrazomine (tetrazomine); thick fructose test (thaliblastine). Thi〇c〇raline; gold plateletin; thrombopoietin mimetic, thy mal fas in; thymosin receptor agonist 'thymotrinan'; Thyroid stimulating hormone; tin ethyl etiopurpurin; ditanocene bichloride, t〇pSentin; translation inhibitor; lS1808.doc -58- 201120037 retinoic acid (tretinoin) (all-trans retinoic acid, such as Vesan〇id®); triethylhydrazine uridine; turosteride; tyrosine kinase inhibitor; tyrosine phosphorylation inhibitor (tyrph〇) Stin); UBC inhibitor; ubenimex' urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; variolin B; velares〇i; Veramine; verdin; vinxaUine; vitaxin; zanoter〇ne; and ziiasc〇rb. For a more extensive discussion of the latest cancer therapies, see (10)/, 18th edition, 2006. See also the Nati〇nal Cancer (NCI) website (http://www.cancer.g0v/drugdicti〇nary/) for a comprehensive list of oncology agents for use as a second active agent, and see us

The Food and Drug AdminiStrati〇n (FDA) website has a list of FDA-approved oncology agents. In other embodiments, the second agent is a supportive care agent such as an antiemetic or red blood cell generating stimulating agent. Specific antiemetic agents include, but are not limited to, phenothiazine, phenol ketone, benzodiazepine, corticosteroids, serotonin antagonists, cannabinoids, and NK1 receptor antagonists. Examples of oxazine antiemetic agents include, but are not limited to, pr〇chl〇rperazine and trioxoylamine. Examples of butyric phenol ketone antiemetics include, but are not limited to, halopeddol. Examples of benzodiazepine antiemetics include, but are not limited to, lorazepam. Examples of corticosteroid antiemetics include, but are not limited to, dexamethasone. Examples of serotonin receptor (5·ΗΤ3 receptor) antagonist antiemetics include, but are not limited to, d〇lasetr〇n mesylate (eg Anzemet®), granisetron (granisetr) 〇n) (eg 151808.doc -59- 201120037

Kytril®), itasetron, ondansetron (eg Zofran®), palonosetron (eg Aloxi®), ramosetron, tesbital (tropisetron) (eg Navoban®), batanopride, dazopride, renzapride. Examples of cannabis-like antiemetics include, but are not limited to, dronabinol. Examples of NK1 receptor antagonists include, but are not limited to, Apre " aprepitant (e.g., Emend®). Other Supportive Care Second agents include agents that stimulate red blood cell production or other hematopoietic processes, such as epoetin alpha (eg Epogen®, Procrit®); G-CSF and recombinant forms such as filgrastim ( Filgrastim) (eg Neupogen®), pegfilgrastim (eg Neulasta®) and lenofilgrastim; darbepoetin alfa (eg Aranesp®); and GM-CSF and Recombinant forms such as sargramostim (eg Leukine®) or molrasostim. Other supportive care agents include chemical protectants such as amifostine (eg Ethyol®), dexrazoxane (eg Zinecard®), leucovorin (aldehyde folate) and guanidine Sodium mesalate (eg Mesnex®); platelet-producing growth factors such as interleukin-11 (IL-11, oprelvekin, eg Neumega®); bisphosphonates such as pamidronate Pamidronate disodium (eg, Aredia®), etidronate disodium (eg, Didronel®), and “zoledronic acid (eg, Zometa®); and TNF antagonists, such as Infliximab (eg Remicade®). lS1808.doc -60- 201120037 Tumor lysis syndrome (TLS) may occur in the treatment of hematological cancer, and a supportive care agent may be administered to a patient treated with a compound of formula I or a hydrazine compound of the invention to alleviate or prevent TLS or Some of its symptoms. Therapeutic agents suitable for preventing or ameliorating TLS (or any of its symptoms, including hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acute renal failure) include, for example, Anle Pulino (all 〇purin〇1) (eg Zyl〇prim®), rasburicase (eg Elitek®) and sodium polystyrene sulfonate (eg Kayexalate®) compound of formula I or compound of formula II and other active second The dosage and dosage regimen of the agent and its combination will depend on the particular condition being treated, the age and condition of the patient, and the severity of the adverse effects, and may be adjusted accordingly by those skilled in the art. Examples of dosages and dosing regimens for other active moieties can be found, for example, in the physician's desk reference (household/^hu•(10), $ is a moxibustion~), and will need to be improved for use in the method of the invention. The active moiety referred to herein as the second agent may be identified as a free active moiety or a salt form (including salts having hydrogen or a coordinate bond) or as a non-covalent derivative of such active moiety (eg, a chelate, Other forms of complexes and clathrates, but it should be understood that a given representative commercial pharmaceutical product is not limiting and may alternatively use a free active moiety, or a sleeping or other derivative form of the active moiety. The active portion referred to is understood to include: only the free active moiety is encompassed, and any pharmacologically acceptable salt or other derivative form which is equivalent to the specified oxime parameter is also encompassed. Pharmaceutical compositions and dosage forms are provided herein. a compound provided as an active ingredient (Package 151808.doc • 61 - 201120037 includes a single enantiomer, a mixture of enantiomers or a mixture of diastereomers thereof) or A pharmaceutical composition of a pharmaceutically acceptable salt, solvate or prodrug in combination with a pharmaceutically acceptable vehicle, carrier, diluent, excipient or mixture thereof. The pharmaceutical composition can be formulated A plurality of dosage forms including, but not limited to, those for oral, parenteral or topical administration. The pharmaceutical compositions may also be formulated as modified release dosage forms including, but not limited to, delayed, prolonged, chronic, sustained, Pulse, control, acceleration and rapid, targeted, stylized release and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Rewingion. rhe Science and

Pharmacy, fSJ _L χ , Modified-Release Drug Deliver Technology, edited by Rathbone et al., Drugs and the; ^",

Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126). In one embodiment, a pharmaceutical composition is provided in a dosage form for oral administration, the compositions comprising a compound provided herein, including a single enantiomer, a mixture of enantiomers or a non- a mixture of enantiomers' or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient or mixture thereof. In another embodiment, pharmaceutical compositions are provided in a dosage form for parenteral administration, the compositions comprising a compound provided herein, including a single enantiomer, a mixture of enantiomers or a mixture of its diastereomers. And a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient or mixture thereof. 151808.doc • 62 - 201120037 In yet another embodiment, a pharmaceutical composition is provided in a dosage form for topical administration. The compositions comprise a compound provided herein, including a single pair, isomer enantiomer a mixture of bodies or a mixture of their diastereomers, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, excipient Or a mixture thereof. The pharmaceutical compositions provided herein can be provided in unit dosage form or in multiple dosage forms. As used herein, unit dosage form refers to a physical individual unit as known in the art that is suitable for administration to an individual and individually encapsulated. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, together with a pharmaceutically acceptable vehicle, carrier, diluent, excipient or mixture thereof. Examples of unit dosage forms include Antec, syringes, and individually encapsulated fasteners and capsules. The unit dosage form can be administered in multiple or multiple portions. Multiple dosage forms are a plurality of identical unit dosage forms that are packaged in a single container and are to be administered in divided unit dosage forms. Examples of multiple dosage forms include vials, lozenges or capsules, and pint or gaH(n) bottles. The pharmaceutical compositions provided herein can be administered in a single dose or multiple times at regular intervals. It will be appreciated that the dosage and duration of treatment appropriate for a particular patient may vary with the age, weight and condition of the patient being treated, and may be tested empirically or by in vivo or in vitro testing or diagnostic data using known testing protocols. Presumed judgment. It should be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the pharmaceutical composition provided herein. A. Oral Administration The compositions (4) provided herein can be used for oral administration of solids, 151808.doc-63-201120037 semi-solid or liquid dosage forms. Oral administration, as used herein, also includes buccal, translingual, and sublingual administration. Suitable oral dosage forms, including (but not limited to) sharp agents, capsules, pills, sugar-coated keys, mouth-containing spine tablets, cachets, pellets, medicated chewable tablets, granules, bulk powders, Foamed or non-foamed powders or granules, solutions, emulsions, suspensions, powders, sprays, elixirs and syrups. In addition to the active ingredient, the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrating agents, wetting agents, lubricating agents Agents, slip agents, colorants, dye migration inhibitors, sweeteners and flavoring agents. The binder or granulating agent imparts cohesiveness to the tablet to ensure that the tablet remains intact after the shrinkage. Suitable binders or granulating agents include, but are not limited to, starches such as corn flour, potato powder and pregelatinized powder (eg starch 1500); gelatin; sugars such as sucrose, glucose, dextrose, Molasses and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extracts, panwar gum, ghatti gum, psyllium husks Isabg〇i husk) glue, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan (Urch arabogalactan), powdered jaundice Gum and guar gum; cellulose such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581 'AVICEL-PH-105 ( FMC Corp., Marcus Hook, 151808.doc • 64 - 201120037 PA); and its mixture is about 1 碳酸 carbonated , M t , cellulose, powdered cellulose, dextrate, high 丄 (1) territory, mannitol, citric acid, sorbitol, starch, pregelatinized powder; 5 甘 /, mixture . In certain embodiments, the binder or locus is present in the pharmaceutical compositions provided herein at a ratio of from about 50 to about 9, reset / °. Suitable dilution b hand agents include, but are not limited to, dicalcium phosphate, calcium sulfate, sugar, sorbitol, zirconium, inositol, inositol, cellulose, kaolin, mannitol, gasification, sodium powder, powder Sugar. Certain diluents, such as mannitol, sugar, sorbitol, sucrose, and inositol, when present in sufficient amounts, can be given to certain compressed tablets by + & 4 p 1 ^ 蛑The property of disintegration in the mouth. These compressed tablets can be used as a chewable ingot. Suitable disintegrants include, but are not limited to, fats; bentonite; cellulose, sulphate-based cellulose and ortho-methylcellulose; wood products; natural sponges; cationic parent-changing trees, alginic acid; gums, such as guar gum And weige gum HV; citrus slag, parent cellulose "such as croscarmellose; cross-linked polymer" such as cross-linked poly-dimensional cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium acetate泊拉可林钟 (p〇lacriHn state (4); 粕, such as corn starch, potato starch, tapioca starch and pregelatinized starch; clay; lignin; and mixtures thereof. The amount of disintegrant in the composition will vary depending on the type of formulation and can be readily discerned by one of ordinary skill. In certain embodiments, the pharmaceutical compositions provided herein contain from about 5 to about 15% by weight or From about i to about 5% by weight of disintegrant. 151808.doc 65· 201120037 Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; sodium stearyl fumarate; mineral oil Light mineral oil; glycerin; sorbose Alcohol, mannitol; glycols such as glyceryl phthalate and polyethylene glycol (PEG); stearic acid; stearin fumarate; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, Cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; stone pine; cerium oxide or tannin, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) ACAB-0-SIL® (Cabot Co., Boston, MA); and mixtures thereof. In certain embodiments, the pharmaceutical compositions provided herein contain from about 〇丨 to about 5 % by weight of lubricant. Suitable slip agents include, but are not limited to, colloidal cerium oxide, cab_0_SIL® (Cabot Co., Boston, ΜΑ) and non-asbestos talc. Colorants include, but are not limited to, any approved, A certified water-soluble FD&c dye, a water-insoluble Fd&c dye suspended on a oxidized hydrate, and a lake, and mixtures thereof. The lake is a combination of a water-soluble dye adsorbed on a heavy metal hydrated oxide, Thereby producing an insoluble form of the dye. These include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic compound blends such as peppermint and decyl salicylate that produce a pleasant taste. Sweeteners include, but are not limited to, sucrose, lactose, Mannitol, syrup, glycerin and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite and surfactants. Such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 151808.doc -66 - 201120037 80 (TWEEN® 80) and triethanolamine oleate. Suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose, pectin, tragacanth, weige gum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl fluorenyl cellulose and polyethylene. Bilo biting ketone. Preservatives include, but are not limited to, glycerin, hydroxybenzoic acid, and benzoic acid, benzoic acid (benzojc a(jd), sodium benzoate, and alcohol. Wetting agents include, but are not limited to, Propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laurel. Solvents include, but are not limited to, glycerin, sorbitol, ethanol and syrup. Examples of non-aqueous liquids utilized include mineral oil and cottonseed oil. Organic acids include, but are not limited to, citric acid and tartaric acid. Sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. It should be understood that even in the same blending The specific carrier or excipient may also serve more than one function. The pharmaceutical composition provided herein may be a compressed tablet, a lozenge, a chewable lozenge, a fast dissolving tablet, a multi-compressed tablet. Provided in the form of a tablet coated with an enteric coated tablet, a coated sugar-coated tablet or a coated film. The coated enteric coated tablet is resistant to gastric acid but dissolved or collapsed in the intestine. Solution A compressed lozenge coated with an active ingredient that is not affected by the acidic environment of the stomach. The enteric coating includes, but is not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated insects. Glue and cellulose acetate phthalate. The coated sugar-coated tablet is a compressed tablet surrounded by a sugar coating, which can be beneficial to cover bad taste or odor and protect the tablet from oxidation. A compressed tablet coated with a thin layer or film of a water-soluble substance. The film coat includes, but is not limited to, hydroxyethyl cellulose, carboxymethyl fiber 151808.doc -67· 201120037 vitamin sodium, polyethylene glycol 4 _ and cellulose acetate phthalate. The film coat gives the same general characteristics as the sugar coat. The multi-compressed tablet is a compressed tablet prepared by one or more compression cycles, including a layered ingot-coated coating agent. And a dry-coated lozenge. The lozenge dosage form can be an active ingredient in the form of a powder, crystal or granule, or a pharmaceutically acceptable vehicle, carrier, diluent or excipient: a mixture thereof (including, for example, a binder) Agent, disintegrant, controlled release It is prepared by a combination of a polymer, a lubricant, a riding agent and/or a coloring agent. Flavoring agents and sweeteners are especially suitable for forming chewable tablets and buccal tablets. The pharmaceutical compositions provided herein may be soft capsules or Provided in the form of hard capsules, such as gelatin, decyl cellulose, pullulan, starch or calcium alginate. Hard gelatin capsules (also known as dry-filled capsules (DFC)) consist of two parts One part of the sleeve is placed on the other part to completely enclose the active ingredient. Soft elastic capsule (Sec) is a soft spherical shell plasticized by adding glycerin, sorbitol or similar polyol, such as gelatin shell. Soft gelatin shell Preservatives which may contain a preservative to prevent microbial growth are as described herein, including but not limited to methylparaben and propylparaben and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions in propyl carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239 and 4,410,545. Capsules may also be coated as known to those skilled in the art to modify or maintain dissolution of the active ingredient. 151808.doc • 68 · 201120037 The medicinal compositions provided herein can be provided in liquid and semi-solid dosage forms. These dosage forms include, but are not limited to, emulsions, solutions, suspensions, susceptories, and syrups. The emulsion is a two-phase system. The H liquid is dispersed in the form of small pellets in another liquid. The two-phase system may be an oil-in-water or water-in-oil emulsion. The emulsion may include a pharmaceutically acceptable non-aqueous liquid or Solvents, emulsifiers and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous solution of xiao may include a pharmaceutically acceptable acetal such as a bis(lower alkyl) acetal of a lower alkyl aldehyde such as acetaldehyde diethyl acetal; and a water miscible solvent having one or more hydroxyl groups, Such as propylene glycol and ethanol. The bismuth agent is a transparent, sweet water alcohol solution. The syrup is a concentrated aqueous solution of a sugar such as sucrose and may also contain a preservative. For liquid dosage forms, for example, the solution in the polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) for convenient measurement for administration. Other suitable liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients provided herein and the dialkylated monoalkylene glycol or polyalkylene glycol, wherein the dialkylated monoalkylene glycol or poly The alkanediol includes 12-dimethoxy oxime, diethylene glycol diterpene, triethylene glycol dioxime ether, tetraethylene glycol dioxin, polyethylene glycol-3 50-didecyl ether, Polyethylene glycol-5 50-dimethyl ether, polyethylene glycol-750-dimethyl ether' wherein 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol ^ such formulations may further comprise one or more Antioxidants such as butylated hydroxyindole (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquine, hydroxycoumarin, ethanolamine, Lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thio 151808.doc -69- 201120037 dipropionic acid and its esters, and disulfide Amino phthalate. The pharmaceutical compositions for oral administration provided herein may also be provided in the form of liposomes, micromicelles, microspheres or nanosystems. The micromicelle dosage form can be prepared as described in U.S. Patent No. 6,350,458. The pharmaceutical compositions provided herein can be provided in the form of non-foamed or expanded granules or powders to be reconstituted into a liquid dosage form. The pharmaceutically acceptable carriers and excipients used in the non-foaming granules or powders may include diluents, sweeteners and wetting agents. The pharmaceutically acceptable carriers and excipients used in the foaming granules or powders may include organic acids, and sources of carbon dioxide. Colorants and flavoring agents can be used in all of the dosage forms described herein. The pharmaceutical compositions provided herein can be formulated for immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release forms. The pharmaceutical compositions provided herein can be formulated with other active ingredients which do not impair the desired therapeutic effect or which are supplemented with substances which supplement the desired effect. B. Parenteral Administration The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for topical or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micromicelles, liposomes, microspheres, nanosystems, and suitable for injection. The solid form previously dissolved or suspended in the liquid 151808.doc 201120037. Such dosage forms can be prepared according to methods well-known to those skilled in the art (see Remingt〇n: The Science and Practice of Pharmacy^ supra). A pharmaceutical composition for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles. Antimicrobial or preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, and dissimilaring agents' spacers against microbial growth Or a chelating agent, a cryoprotectant, a lyoprotectant, a thickener, a pH adjuster, and an inert gas. Suitable sigma-based aqueous vehicles include, but are not limited to, water, saline, physiological saline or phytate buffered saline (PBS), sodium carbonate injection, Ringer's injection, isotonic dextrose injection, Sterilized water injection, as well as dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, plant-derived fixed oils, lotus oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, A chain of triglycerides in coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanol, liquid polyethylene glycols (eg, polyethylene glycol 3 oxime and polyethylene glycol 400), propanol, glycerin, N - mercapto-2-pyrrolidone, N, N_: methyl acetamide and disulfoxide. Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, amalgam, benzofuran, chlorobutanol, methyl p-hydroxybenzoate and propyl paraben, thimerosal, gasified benzene Ammonium methane (benzalk〇nium chl〇_ 151808.doc -71 - 201120037 ride) (eg benzethonium chloride), p-alkyl perbenzoate and p-propyl benzoate, and sorbic acid . Suitable isotonic agents include, but are not limited to, sodium, glycerin and dextrose. Suitable buffering agents include, but are not limited to, acidates and citrates. Suitable antioxidants are as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, pr〇caine hydr〇chl〇ride. Suitable suspending and dispersing agents are those as described herein, including sodium sulphonate, hydroxypropyl methylcellulose, and polyethylene pyrrolidinone. Suitable emulsifiers include those described herein. Including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 8 oxime and triethanolamine oleate. Suitable spacers or chelating agents include, but are not limited to, EDTA. pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha cyclodextrin, beta-cyclodextrin, hydroxypropyl Base·β_cyclodextrin, sulfobutyl ether _ρ_cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS). , , the medicine provided herein The compositions may be formulated for single-dose or multi-dose administration. Single-dose formulations may be packaged, for example, in ampoules, vials or syringes. In certain embodiments, multi-dose parenteral formulations contain bacteriostatic or An antimicrobial agent at a fungicidal concentration. In certain embodiments, such The parenteral formulation provided herein is known in the art and is embodied as a helminth. In an embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the f-agent The composition is provided as a sterile anhydrous soluble product form 151808.doc -72 - 201120037 (including lyophilized powders and subcutaneous lozenges) for reconstitution with a vehicle prior to use. In another embodiment, the pharmaceutical composition is Provided in the form of a sterile suspension. In another embodiment, the pharmaceutical composition is provided in the form of a sterile anhydrous insoluble product for reconstitution with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is sterile in ready-to-use form Provided in the form of an emulsion. The pharmaceutical compositions provided herein can be formulated in an immediate release or modified release dosage form, including delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release forms. Formulated in the form of a suspension, solid, semi-solid or lyotropic liquid for administration in the form of an implantable reservoir. In one embodiment, the pharmaceutical compositions provided herein Dispersed in the solid internal matrix surrounded by the outer polymeric film, the outer polymeric film is insoluble in the body fluid, but allows the active ingredient in the pharmaceutical composition to diffuse through. The palatable internal matrix includes polydecyl methacrylate, poly Butyl methacrylate, plasticized or unplasticized polystyrene 1 plastic plastieized coffee, plastic polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene , polybutylene dilute, polyethylene, ethylene-acetic acid ethylene vinegar copolymer, poly-stone oxide rubber, polydimethyl oxalate, poly-stone oxyacetate copolymer, hydrophilic polymer (such as C Hydrogel of dilute acid and methacrylic acid vinegar), collagen, cross-linked polyethylene glycol, and partially hydrolyzed cross-linked polyacetic acid. Suitable for outer polymer film including polyethylene, polypropylene , ethylene/propylene copolymer, ethylene/acrylic acid ethylene-copolymer 'ethyl acetate sulphuric acid copolymer, poly-stone oxide rubber, polydimethyl sulphur oxide, gas rubber, gasification polyethylene 151808 .doc •73· 201120037 olefin, polyvinyl chloride, ethylene and acetic acid Ester copolymer, vinylidene chloride, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate / ethylene An alcohol diterpene copolymer, and an ethylene/vinyloxyethanol copolymer. c. Topical Administration The pharmaceutical compositions provided herein can be administered topically to the skin, orifice or mucosa. As used herein, topical administration includes dermal (internal), conjunctival, intracornal, intraocular, transocular, otic, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration. The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration to produce a local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings ( Dressing, elixirs, lotions, suspensions, elixirs, pastes, foaming agents, films, aerosols, irrigation, sprays, suppositories, bandages and dermal patches. The topical formulations of the pharmaceutical compositions provided herein may also comprise liposomes, micromicelles, microspheres, nanosystems, and mixtures thereof. Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobials against microbial growth Or preservatives, stabilizing agents, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, spacers or chelating agents, penetration Enhancer, cryoprotectant, lyoprotectant, extender and inert gas. The pharmaceutical composition can also be electroporated, iontophoresis 151808.doc • 74· 201120037 (iontophoresis), ultrasonic drug penetration therapy (ph〇n〇ph〇resis), ultrasonic sonophoresis (sonophoresis) or Micro-administered with a needle or needle-free injection (such as POWDERJECTTM (Chiron Corp., Emeryville, CA) and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin OR)). The pharmaceutical compositions provided herein can be provided in the form of an ointment, cream or gel. Suitable ointment vehicles include oily or hydrocarbon vehicles including lard, benzoin lard, olive oil, cottonseed oil and other oils; white petrolatum; emulsifiable or adsorbent vehicles such as hydrophilic Paraffin oil, hydroxystearin sulfate and anhydrous lanolin; water-removable vehicles such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of different molecular weights; A vehicle, ie a water-in-oil (W/O) emulsion or an oil-in-water (〇/w) emulsion, including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see heart (5) ☆ zewce And corpse (four) to less, same as above). These agents are emollients, but usually require the addition of antioxidants and preservatives. Suitable cream bases can be of the oil-in-water or water-in-oil type. The cream vehicle can be water washable and contains an oil phase, an emulsifier and an aqueous phase. The oil phase is also known as the "internal" phase, which typically contains paraffinic oils and fatty alcohols such as cetyl alcohol or octadecyl alcohol. The aqueous phase generally exceeds the oil phase in volume, but this is not necessarily the case and usually contains a humectant. The emulsifier in the cream formulation may be a nonionic surfactant, an anionic surfactant, a cationic surfactant or an amphoteric surfactant. The gel is a semi-solid, suspension type system. Single-phase gels contain organic macromolecules that are substantially uniform throughout the liquid carrier, 151808.doc -75- 201120037. Suitable gelling agents include crosslinked acrylic polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®, hydrophilic polymers such as polyethylene oxide, polyethylene oxide. Polyoxypropylene copolymer and poly-alcohol; cellulose polymer, such as propyl propyl cellulose, phenylethyl cellulose, propyl propyl methyl cellulose, phthalic acid Cellulose and methylcellulose; gums, such as tragacanth and trisin; sodium alginate; and gelatin. To prepare a uniform gel, a dispersing agent such as an alcohol or glycerin may be added, or the gelling agent may be dispersed by wet grinding, mechanical mixing and/or agitation. The pharmaceutical compositions provided herein may be suppositories, pessaries, probes, lozenges or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, The form of a tampon, gel, foaming agent, spray or enemas is administered rectally, transurethostically, vaginally or vaginally. Such dosage forms can be made using the conventional processes described in the text - (10)d Pra State α 0/ ^, 叮, 席2. Rectal, urethral and vaginal suppositories are solids for insertion into the body orifice which are solid at ambient temperature but which melt or soften at body temperature to release the active ingredient inside the orifice. Pharmaceutically acceptable carriers for use in rectal and vaginal suppositories include a matrix or vehicle, such as a hardening agent, which produces a melting point near body temperature. Suitable vehicles include, but are not limited to, cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethylene glycol), cetyl wax, paraffin wax, white wax and yellow wax, and fatty acid monoglycerides, diacids. Suitable glycerides and triglycerides 151808.doc • 76· 201120037 Mixtures, hydrogels (such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid) and glycerin gelatin. A combination of various vehicles can be used. Rectal and vaginal suppositories may further comprise an antioxidant as described herein comprising bisulfite and sodium metabisulfite. Rectal and vaginal suppositories can be prepared by compression or molding. Typical qualities of rectal and vaginal suppositories range from about 2 g to about 3 g. The pharmaceutical compositions provided herein can be administered ocularly in the form of solutions, suspensions, ointments, lotions, gelling solutions, solutions for powders, gels, ocular inserts or implants. The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical composition can be used alone or in combination with a pressurized container 'pump, shower, atomizer (such as an atomizer that uses electrohydrodynamics to produce a fine mist) or spray (d) to deliver a gas solute or solution. A propellant (such as u, 1, 2, tetrafluoroethane or heptafluoropropene) is provided in combination. The pharmaceutical compositions may also be provided in the form of a dry powder for insufflation, either alone or in combination with an inert carrier such as lactose or phospholipid; or in the form of a nasal drop. For intranasal use, powders can be used to make bio-adhesives, including polyglucosamine or cyclodextrin. A solution or suspension for use in a pressurized container, bombardment, spray, nebulizer or nebulizer may be formulated to contain ethanol, an aqueous ethanol solution, or (4) dispersed, dissolved or extended release provided herein. An alternative pharmaceutical agent or solvent system for the active ingredient; and/or as a propellant for the solvent; and/or a surfactant such as sorbitan trioleate, oleic acid or oligomeric lactic acid. 151808.doc -77· 201120037 The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 丨〇 microns or less. Such sized particles can be prepared using comminuting methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing for forming nanoparticles, high pressure homogenization. Or spray drying method.

I Capsules, foaming agents and cartridges for use in an inhaler or insufflator may be formulated to contain a pharmaceutical composition, a suitable powder base (such as lactose or starch), and a performance modulating agent (such as white) as provided herein. A powder mixture of aminic acid, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions for inhaled/intranasal administration provided herein may further comprise suitable flavoring agents (such as menthol and levomentin) or sweeteners (such as saccharin or sodium sulphate) provided herein. Pharmaceutical compositions for topical administration can be formulated for immediate release or modified release, including delayed release, sustained release, pulsed release, controlled release, targeted release, and stylized release. D. Modified Release The pharmaceutical compositions provided herein can be formulated in a modified release dosage form. As used herein, the term "modified release" refers to a dosage form that, when administered by the same route, has a rate or location of release of the active ingredient that is different from the immediate dosage form. Modified release dosage forms include delayed, extended, long-term, sustained, pulsed, controlled, accelerated, and rapid, targeted, stylized release, and gastric retention dosage forms. The pharmaceutical compositions of the modified release dosage form of 151808.doc-78-201120037 may employ a variety of modified release devices and methods known to those skilled in the art including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulates. Prepared by controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by altering the particle size and polymorphism of the active ingredient. Examples of modified release include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; , No. 5, 639, 476; No. 5, 639, 560; No. 5, 639, 480; No. 5, 733, 566; No. 5, 739, pp; No. 5, 891, 474; No. 5, 922, 356; No. 5, 972, 891; No. 5, 980, 945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358 ; and those described in No. 6,699,500. 1. Matrix Controlled Release Devices Pharmaceutical compositions in modified release dosage forms provided herein can be made using matrix controlled release devices known to those skilled in the art (see Takada et al., "Encyclopedia of Controlled Drug Delivery", Volume 2, edited by Mathiowitz, Wiley, 1999). In one embodiment, an erosive matrix device is used to formulate a pharmaceutical composition in a modified release dosage form as provided herein, which is swellable and erosable in water 151808.doc -79 - 201120037 Sexual and/or soluble polymers, including synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins. Suitable materials for forming an erodible substrate include, but are not limited to, chitin, polyglucamine, dextran and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth, horn Fork, Gum, Guar, Sanxian and scleroglucan; starch, such as dextrin and maltodextrin; hydrophilic colloid, gelatin; phospholipids such as lecithin; alginate; Propylene glycol alginate; gelatin; collagen; and cellulosics such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxyl Propylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmercaptoacetate (HPMCAT) and ethylhydroxyethylcellulose (EHEC); polyethylene D Polyethylene, polyethylene acetate, fatty acid glycerol, polyacrylamide, polyacrylic acid, ethyl acrylate or nail Copolymer of acrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactide; L- faceted acid and ethyl L-glutamate Copolymer; degradable lactic acid-glycolic acid copolymer; poly_D_(_)_3-hydroxybutyric acid; and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate A homopolymer and a copolymer of ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate. 151808.doc • 80- 201120037 In certain embodiments, the pharmaceutical composition is formulated with a non-erodable matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, once administered, is primarily released by diffusion through an inert matrix. Substances suitable for use as non-invasive matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, poly Butyl methacrylate, vaporized polyethylene, polyethylene, methacrylate-mercapto methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, gas Copolymer of ethylene and vinyl acetate, ethylene diene, ethylene and propylene, polyethylene terephthalate ionomer, butyl rubber, surface alcohol rubber, ethylene/vinyl alcohol copolymer, ethylene / Vinyl acetate/vinyl alcohol terpolymer and ethylene/vinyloxyethanol copolymer, polyethylene, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyoxyethylene rubber, poly a methyl methoxy oxane, a polyoxy oxycarbonate copolymer; a hydrophilic polymer such as ethyl cellulose, cellulose acetate, crospovidone and partially hydrolyzed crosslinked polyvinyl acetate; and an aliphatic compound 'such as carnauba wax, 胄Crystal wax and triglyceride. In a matrix controlled release system, for example, via the type of polymer used, the viscosity of the polymer, the particle size of the polymer and/or active ingredient, and the activity

The ratio of parts to polymer and other excipients or carriers in the composition to control the desired release power D. The pharmaceutical compositions provided herein in modified release dosage forms can be prepared by methods known to those skilled in the art. These methods include direct compression, post-dry or wet granulation, or melt granulation (meh_151808.doc 81 201120037 granulation) followed by compression. 2. Osmotic Controlled Release Devices Pharmaceutical compositions in modified release dosage forms provided herein can be made using osmotic controlled release devices including single chamber systems, dual chamber systems, asymmetric membrane technology (AMT), and extruded cores. System (ECS). Typically, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one transfer crucible, the semipermeable membrane encapsulating core. The semipermeable membrane controls the flow of water from the aqueous environment into the core to cause drug release by squeezing through the delivery sputum. In addition to the active ingredient, the core of the osmotic device also includes a penetrant, which produces a driving force for transporting water from the environment of use to the core of the device. One type of penetrant is a water-swellable hydrophilic polymer, also known as "osmopolymer" and "hydrogel", including but not limited to hydrophilic ethylene and acrylic polymers, Polysaccharides, such as alginic acid, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(methyl acrylate), poly(acrylic acid), Poly(mercaptopropyl) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymer, having a hydrophobic single such as methyl methacrylate and vinyl acetate PVA/PVP copolymer, hydrophilic polyurethane with large PEO block, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl decyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, sin And sodium starch via sodium acetate. 151808.doc • 82 · 201120037 Another class of penetrants includes zymogens that are capable of inhaling water to affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable zymogens include, but are not limited to, inorganic salts such as sulfuric acid, gasification, gasification, sodium chloride, gasification clock, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, gasification and unloading And sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids, such as anti-bad enterprises Acid, benzoic acid, anti-butadiene _ acid, citric acid, maleic acid, azelaic acid, sorbic acid, adipic acid 'edic acid, face acid, p-toluenesulfonic acid, succinic acid And tartaric acid; urea; and mixtures thereof. Penetrants of different dissolution rates can be used to influence how the active ingredient is rapidly delivered from the initial dosage form. For example, amorphous sugars such as Mann(R) GEmtm EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first 2 hours to rapidly produce the desired therapeutic effect, and the remaining amount is gentle and sustained release. In order to maintain the therapeutic or prophylactic effect level for an extended period of time, the active ingredient is released at a specific rate, thereby replacing the amount of the metabolically and excreted active ingredient. The core may also include a variety of other excipients and carriers as described herein to enhance dosage form efficacy or to promote stability or handling. Substances suitable for forming semipermeable particles include various grades of acrylic acid, vinyl, hydrazine, polyamine, polyglycol and cellulose derivatives which are water permeable at physiologically relevant pH values. Water is insoluble or readily becomes water insoluble by chemical changes such as cross-linking. Examples of suitable polymers suitable for forming a coating include, but are not limited to, plasticized, unplasticized, and reinforced acetic acid 151808.doc -83· 201120037 Cellulose (CA), cellulose diacetate, triacetate fiber , cellulose acetate propionate, cellulose nitrate, cellulose acetate butyrate (CAB), cellulose acetate ethyl decanoate, CAP, cellulose acetate methyl formate, cellulose acetate succinate, acetic acid Cellulose triglyceride (CAT), cellulose dimethylaminoacetate, cellulose acetate ethyl acetate, acetic acid, cellulose acetate, cellulose acetate, ethyl oxalate, cellulose acetate, methyl acetate, cellulose acetate Continuous acid butyl ester, acetic acid p-toluene cellulose acetate, acetic acid lipopolysaccharide, triacetic acid amylose, acetic acid beta glucan, triacetic acid beta glucan, acetaldehyde diacetate, locust bean gum triacetic acid Ester, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acid and ester, poly( Methacrylic acid and esters and copolymers thereof, starch, Portuguese Sugar, dextrin, poly saccharide glucosamine, collagen, knees out, of polyolefin, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes. The semipermeable membrane may also be a hydrophobic microporous membrane wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium and may be infiltrated by water vapor as disclosed in U.S. Patent No. 5,798,1, 19. The hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, Polystyrene, polyhalogenated ethylene, polyvinylidene fluoride, polyvinyl ester and ether, natural hydrazine and synthetic hydrazine. The transfer imperfections on the semipermeable membrane can be formed by mechanical or laser drilling after the coating. The transfer enthalpy can also be formed by eroding the embedding of the water-soluble substance or by breaking the thinner portion of the film through the indentation on the core 151808.doc • 84- 201120037. In addition, the transfer enthalpy can be formed during the coating process, as described in the case of the asymmetric film coating, as described in U.S. Patent Nos. 5,612,059 and 5,698,220. The total amount and rate of release of the active ingredient released can be adjusted by adjusting the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size and location of the delivery enthalpy. Pharmaceutical compositions in the form of osmotic controlled release dosage forms may further comprise other conventional thief-shaped agents or carriers as described herein to facilitate the performance or handling of the formulation. The osmotic controlled release dosage form can be prepared according to conventional methods and techniques known to those skilled in the art (see heart for training. r/2e palpitations (9) to (10) j (3) palpitations /, above; Santus and return" , ^

Release 1995, 35, 1-21; Verma f Λ , and Industrial Pharmacy 2000, 25, 695-708 ; Verma# A, J.

Controlled Release 20Q2, 79, . In certain embodiments, the pharmaceutical compositions provided herein are formulated in a controlled release dosage form comprising an asymmetric osmotic membrane coated with a core comprising the active ingredient and other pharmaceutically acceptable excipients or carriers. . See U.S. Patent Nos. 5,612, 〇 59 and W〇 2〇〇 2/17918. The amt controlled release dosage form can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation or dip coating methods. In certain embodiments, the pharmaceutical compositions provided herein are formulated in an ESC controlled release dosage form comprising a coating from & uj 匕 complex 3 active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable It is also permeable to the core of the excipient or carrier of 151808.doc -85- 201120037. 3. Multiparticulate Controlled Release Devices Pharmaceutical compositions in modified release dosage forms provided herein can be made using a multiparticulate controlled release device comprising a diameter of from about 10 μm to about 3 mm, about 50 μm. A plurality of particles, granules or pellets ranging from about 2.5 mm or from about 1 〇〇 μηη to about 1 mm. Such multiparticulates can be prepared by processes known to those skilled in the art, including wet and dry granulation, extrusion/spheronization, rolling, melt freezing, and by spraying a seed core. See for example MM/iipariicw/aie <9ra/

Marcel Dekker: 1994; and corpse/mrmacewiz'ca/

Marcel Dekker: 1989. Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in the treatment and formation of the multipartum. The resulting particles may themselves constitute a multiparticulate device, or may be coated with various film forming materials such as casing polymers, water-swellable polymers, and water-soluble polymers. The multiparticulates can be further processed into capsules or lozenges. 4. Delivery The pharmaceutical compositions provided herein can also be formulated to target specific tissues, receptors or other regions of the body in which the individual is to be treated, including liposome-based, resealed red blood cells, and antibody-based delivery systems. . Examples include, but are not limited to, U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; U.S. Patent Nos. 6,060, 082; 6,048, 736; 6,039, 975; 6, 004, 534; 5, 985, 307, 151, 808. doc, pp. 86-201120037, pp. 5, 980, 366; 5,900, 252; 5, 840, 674; 5, 759, 542; and 5, 709, 874 Delivery system. It is to be understood that the foregoing detailed description and the accompanying claims Such changes and modifications can be made without departing from the spirit and scope of the invention, including but not limited to variations and modifications relating to the methods of use provided herein. The patents, patent publications, and other publications referred to herein are hereby incorporated by reference. EXAMPLES All commercially available starting materials and solvents were reagent grade or better and were used without further purification. Synthesis of Compound A

Compound A Step-1: Synthesis of Compound A1

Compound A1 To a solution of N-decanesulfonylpiperidine (23.77 g, 145.6 mmol) in tetrahydrofuran (THF) (150 mL) was added dropwise n-butyllithium (2.6 in hexane) at -78 °C. Μ solution, 56 mL '145.6 mmol) and at the same temperature, 151808.doc •87- 201120037 The reaction mixture was mixed for 1 hour. Then 2,6-dichloropyridyl was added dropwise. A solution of methyl formate (20 g' 97 mmol) in THF (150 mL) was applied and the reaction mixture was then allowed to stand for 2 hrs during which time the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with a saturated ammonium sulphate solution and then extracted with EtOAc (EtOAc). The organic layer was dried with EtOAc (EtOAc) 1H NMR (300 MHz, CDC13): 8.0 (d, 8 Hz, 1H), 7.4 (d 8 Hz, 1H), 4.6 (s, 2H), 3.3 (br t, 4 Hz, 4H), 1, 7 (br s, 6H). LC/MS (M+H)+ 337, 339 Step-2: Synthesis of Compound A2

Compound A2 was heated at 140 ° C for a mixture of compound Al (10 g '29.6 mmol), triethyl orthoformate (15 mL '90 mmol) and acetic anhydride (21 mL, 222 mmol) for 5 h during the period at atmospheric pressure The obtained Et 〇Ac was distilled off under force. It was then concentrated under reduced pressure and the residue was diluted with THF (60 mL). 2_Aminothiazole (3.27 g, 32.6 mmol) was added thereto and then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was tribr. The resulting yellow solid was collected by EtOAc, washed with diethyl ether and dried. Yield: 1〇2 • Ο (77%) 〇 Step-3: Synthesis of the compound 151 151808.doc -88- 201120037 r\

K2CO3 / Dioxane "" ^ Cl

Into the compound Α2 (1·9 g, 4.25 mmol) in dioxane (20 mL), and the mixture was added with carbonic acid (0.88 g ' 6.37 mmol) and stirred at 60 ° C. The reaction mixture was held for 1 hour. Next, the reaction mixture was filtered to remove potassium carbonate and the filtrate was concentrated. The residue was partitioned between di-methane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate By column chromatography (Shishijiao 60-120 mesh) with 0-15 ° /. The residue was purified by EtOAc (EtOAc) elute Yield: 1.2 g (68.7%). 1H NMR (300 MHz, CDC13): 10.0 (s, 1H), 8.7 (d, 8Hz, 1H), 7.7 (d, 3.5Hz, 1H), 7.5 (d, 8Hz, 1H), 7.4 (d, 3.5Hz) , 1H), 3.4 (br s, 4H), 1.7 (br s, 6H) 〇LC/MS (M+H)+ 411, 413 Synthesis of Compound B n V,+

Step-1: Synthesis of Compound B1

151808.doc • 89- 201120037 n-Butyllithium was added dropwise to a solution of N,N-dimethylmethanthine (18 g, 146 mmol) in THF (150 mL) at -78 °C. (2.6 Μ solution in hexanes, 56 mL, 145.6 mmol) and the mixture was stirred at the same temperature for one hour. Then a solution of 2,6-dichloropyridin-3-carboxylate (20 g, 97 mmol) in THF (150 mL) was added dropwise and the reaction mixture was stirred for a further 16 s. Room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride and then extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated to give a white crystal. The product was washed with diethyl ether and petroleum ether and dried in vacuo. Yield: 22 g (76%). 1H NMR (300 MHz, CDC13): 8.0 (d, 8 Hz, 1H), 7.4 (d, 8 Hz, 1H), 4.6 (s, 2H), 3.0 (s, 6H). LC/MS (M+H)+ 295, 297 Step-2: Synthesis of Compound B2

A mixture of compound bi (22 g, 74 mmol), triethyl orthoformate (30 mL, 180 mmol) and acetic anhydride (45 mL·, 470 mmol) was heated at 140 C for 4 h during the period at atmospheric pressure The obtained Et〇Ac was distilled off. It was then concentrated under reduced pressure and the residue was dissolved in THF (12 mL). 2-Aminothiazole (8 g, 8 〇 mm〇i) was added thereto and then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was evaporated to ethyl ether. The resulting yellow solid was collected by filtration, washed with diethyl ether and dried. Yield: 23 g (76%). 151808.doc •90- 201120037 Step-3: Synthesis of Compound B

K2C03 / Dioxane \=J Compound B2

To a solution of Compound B2 (23 g, 56.5 mmol) in EtOAc (EtOAc) (EtOAc) (EtOAc) Next, the reaction mixture was filtered to remove potassium carbonate and the filtrate was concentrated. The residue was partitioned between di-methane and water. The organic layer was separated, washed with water and brine: dried over sodium sulfate and concentrated. The residue was purified by column chromatography eluting EtOAc EtOAc EtOAc Yield: 18 g (86 ° / 〇). 1H NMR (300 MHz, CDC13): 10.0 (s, 1H), 8.7 (d, 8Hz, 1H), 7.7 (d, 3.5Hz, 1H), 7.5 (d, 8Hz, 1H), 7.4 (d, 3.5Hz) , 1H), 3.0 (s, 6H). LC/MS (M+H)+ 371,373. Synthesis of Compound C

/AcOH/THF h2n

O

K2C03 / dioxane o

Step-1: Synthesis of Compound Cl 15l808.doc -91 · 201120037

n-Butyl was added dropwise to a solution of diisopropylamine (23.5 mL '167.7 mmol) in THF (400 mL). And the reaction mixture was given at the same temperature for 3 minutes (min). The reaction mixture was then cooled to -78 ° C and 2,6-di-gas pyrazine was added dropwise over a period of 1.5 hours (1 〇 § '67111111 〇1) Solution in Ding 7 (40〇1^) "The reaction mixture was stirred for an additional hour. Then the reaction mixture was poured onto dry ice and allowed to warm to room temperature over a period of about 16 hours. The reaction mixture was treated with EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) The product thus obtained was used in the next step without further purification and was used in the next step. Yield: about 9 g (69.5%). 1H NMR (300 MHz, DMS 〇 _d6): 8·9 (s, 1H) Step 2 : Synthesis of Compound C2

To a solution of 2,6-dichloropyrazine_3_carboxylic acid (9 g, 46.6 mmol) in dioxane (250 mL) dropwise at room temperature (RT) (5.2 mL) , 61,5 mmol), then DMF (3 drops) was carefully added and then the reaction mixture was stirred at RT for 3 h. It was then concentrated in a rotary evaporator and the residue of 151808.doc • 92- 201120037 was dissolved in toluene (150 mL) and added dropwise to ethyl 3-dimethylaminoacrylate (8.5 g, 59.4 mmol). The mixture was stirred in a mixture of triethylamine (9 7 mL, 69.5 mmol) and stirred at 9 ° C for 16 h. Then, the reaction mixture was cooled, filtered and the filtrate was concentrated. The residue was purified by column chromatography eluting with EtOAc (EtOAc) Yield: 6.7 g (45 ° / 〇). 1H NMR (300 MHz, DMSO-d6): 8.8 (s, 1H), 8.0 (s, 1H), 3.8 (q, 5Hz, 2H), 3.4 (s, 3H), 3.0 (s, 3H), 0.9 ( t, 5Hz, 3H) 〇LC/MS (M+H)+ 318, 320 Step-3: Synthesis of Compound C3Ο

Compound C2

/ AcOH/THF

N-human SW/Compound C3 To a solution of compound C2 (ll g, 34.5 mmol) and 2-aminothiazole (34 g, 34 mmol) in THF (~ 130 mL) The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then filtered and concentrated, %s; The residue was partitioned between Et 〇Ac and water. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc Yield: 5.2 g (40.4%). Step-4: Synthesis of Compound C 151808.doc -93- 201120037

Cl Zheng K2C03 / Dioxane

N \=j compound C3

Cl

\=J Compound c To a solution of compound C3 (5.2 g, 13.9 mmol) in dioxane (50 mL) was added (2_9 g '21 mmol) and the mixture was stirred at 6 〇t: 6 hours. The reaction mixture was then filtered to remove potassium carbonate and the filtrate was concentrated. The residue was partitioned between water and water; the organic layer was separated, dried over sodium sulfate and concentrated. The residue was wet-milled with decyl alcohol and the resulting yellow solid was collected by filtration and dried in vacuo. Yield: 4.5 g (96%). 1H NMR (300 MHz, DMSO_d6): 9.7 (s, 1H), 9.1 (s, 1H). 7.9 (dd, 2.6 Hz, 2H), 4.3 (q, 5 Hz, 3H), 1.3 (t, 5 Hz, 3H) . LC/MS (M+H)+ 337, 339. The general procedure for the reaction of the compound A and the compound B with an amine is added to a solution of the compound A or the compound Β (0·25 g, 1 equivalent) in acetonitrile (5 - 10 mL) at room temperature (15 equivalents) Diisopropylethylamine (4 equivalents for the free amine and 6 equivalents for the amine salt) and the reaction mixture was heated to 80 C. Upon heating, the reaction mixture became clear and a pale yellow solid precipitate was observed after about 15 _ 3 〇. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was then collected by filtration, washed with acetonitrile and dried in vacuo. The filtrate contains varying amounts of product depending on the solubility of the product in acetonitrile. Since the initial harvest was sufficient for the purpose of our purposes, no additional amounts of product were recovered from the filtrate. 15I808.doc -94· 201120037 Example 1 9 〇. .〇

Add diisopropylethylamine (0,5 mL, 2.87 mmol) and 595 J (0-321 g, 0.68 mmol) to a solution of the compound EtOAc (0. 2 g, 0.48 mmol) in EtOAc (5 mL) And the reaction mixture was stirred at 80 ° C for 3 hours. Heating was then stopped and the reaction mixture was allowed to stand overnight, during which time a solid precipitate appeared. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 505. The NMR spectrum is provided in Figure 1. Yield: 0.15 g (61 ° / 〇. Example 2

Diisopropylethylamine (0.34 mL ' 1.95 mmol) and 1-(2·pyridyl)piperazine were added to a solution of Compound A (0.2 g, 0.48 mmol) in EtOAc (5 mL) 0.119 g' 0.73 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 538. The NMR spectrum is provided in Figure 2. Yield: 0.16 g (61%). 151808.doc •95· 201120037 Example 3

Diisopropylethylamine (0.34 mL, 1.95 mmol) and 1-cyclohexyl base were added to a solution of Compound A (0.2 g'0·48 mmol) in acetonitrile (5 mL). Qin (〇, 123 g '0.73 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 543. The NMR spectrum is provided in Figure 3. Yield: 0.19 g (72 ° / 〇). Example 4

Add diisopropylethylamine (0.34 mL, 1.95 mmol) and 1-(4-trifluoromethylphenyl) to a solution of Compound A (0.2 g, 0.48 mmol) in EtOAc (5 mL) Piperazine (0.168 g, mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo 151 808. LC/MS: (M+H)+: 605. The NMR spectrum is provided in Figure 4. Yield: 0.13 g (44 ° / 〇). Example 5

Add diisopropylethylamine (0.42 mL '2.4 mmol) and (R)-(-)-2 to a solution of Compound A (0.25 g '0.60 mmol) in acetonitrile (5 mL). Methylpyrazine (0.092 g, 0.92 mmol) and the reaction mixture was heated to 80 C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 475. The NMR spectrum is provided in Figure 5. Yield: 0.14 g (49%). Example 6

To a solution of the compound A (0.3 g '0.73 mmol) in acetonitrile (6 mL) was added diisopropylethylamine (0.5 mL, 2.9 mmol) and cis-2,6- fluorenyl The azine (0.125 g, 1.09 mmol) and heating the reaction mixture to 80 ° C °, the reaction mixture became clear and solid precipitation began to be observed after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled to 151808.doc •97·201120037. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 489. The NMR spectrum is provided in Figure 6. Yield: 0.26 g (73%). Example 7

Add diisopropylethylamine (0.42 mL, 2.4 mmol) and (R)-3-(dimethylamino) to a solution of Compound A (0.25 g, 0.60 mmol) in EtOAc (5 mL) Pyrrolidine (0.105 g, 0.92 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 489. The NMR spectrum is provided in Figure 7. Yield: 0_24 g (81%). Example 8

To a solution of Compound A (0.25 g, 0.60 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.42 mL, 2.4 mmol). 0.077 g, 0.90 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and after about 15 minutes it was observed to start 151808.doc -98 - 201120037. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (Μ+Η) + : 46〇. The NMR spectrum is provided in Figure 8. Yield: 0.21 g (; 75%). Example 9

Add diisopropylethylamine (0.42 mL, 2.4 mmol) and 4-(1-pyridyl) to a solution of Compound A (0.25 g ' 〇.6 〇mmol) in acetonitrile (5 mL). π each D base) piperidine (0.14 g, 0.91 mmol) and the reaction mixture was heated to 80 C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 529. The NMR spectrum is provided in Figure 9. Yield: 0.24 g (75 ° / 〇). Example 10

Add diisopropylethylamine (0.42 mL, 2.4 mmol) and (S)-2-(A) to a solution of Compound A (0.25 g, 〇·6〇mmol) in acetonitrile (6 mL). Oxymethyl)pyrrolidine (0.105 g '0.91 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and after about 15 minutes 151808.doc -99· 201120037 It was observed that solid precipitation began to appear. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 490. The NMR spectrum is provided in Figure 1A. Yield: 0.21 g (70%) ° Example 11 On η

Add diisopropylethylamine (0.42 mL, 2.4 mmol) and (R)-2-(methoxymethyl) to a solution of the compound oxime (0.25 g, 0.60 mmol) in EtOAc (6 mL) Base 〇 唆 唆 (0.1 〇 5 g, 0.91 mmol) and the reaction mixture was heated to 80. (: When heating, the reaction mixture became clear and solid precipitation began to be observed after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The obtained solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 490. NMR spectrum is provided in Figure 11. Yield: 0.23 g (77°/〇) »

Add diisopropylethylamine (0.42 mL, 2.4 mmol) and (R)-3-aminoindolodine to a solution of Compound A (0.25 g, 0.60 mmol) in EtOAc (6 mL) (0.079 g, 0.92 mmol) and the reaction mixture was heated to 151808.doc -100 - 201120037 80 °C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 461. The NMR spectrum is provided in Figure 12. Yield: 0.27 g (96 ° / 〇). Example 13 9 〇' , 〇

To a solution of Compound A (0.25 g, 0.60 mmol) in EtOAc (6 mL), diisopropylethylamine (0.42 mL, 2.4 mmol) and 3-pyrrole (0.08 g ' 0.92 mmol) And the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and after about 15 minutes it was observed that solid onset began to appear. "The heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 462. The NMR spectrum is provided in Figure 13. Yield: 0.23 g (82 ° / 〇). Example 14

Add diisopropylethylamine (0.42 mL, 2.4 mmol) and 3-(diethyl 151808.doc 201120037 amine base) to a solution of compound A (0.25 g, 0.60 mmol) in EtOAc (6 mL) ) Bipiridine (0.13 g '0.91 mm〇l) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration and washed with acetonitrile and dried in vacuo. LC/MS: (Μ+Η)\ 517. The NMR spectrum is provided in Figure 14. Yield: 0.3 g (95 ° / 〇). Example 15 9 ο. 〇

To a solution of Compound A (0.25 g '0.60 mmol) in acetonitrile (6 mL) at rt, diisopropylethylamine (0.42 mL, 2.4 mmol) and ???· (0·08 g, 0.92 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and a solid sag began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration and washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 462. The NMR spectrum is provided in Figure 15. Yield: 0.26 g (93%). Example 16

Add Diisopropylethylamine (0.42 mL '2.4 mmol) and l- to the solution of Compound A (0.25 g, 0.60 mmol) in acetonitrile (6 mL) at 151808.doc -102·201120037. Boc-piperidone (0.17 g '0 91 mm 〇1) and the reaction mixture was heated to 8 〇c>c. Upon heating, the reaction mixture became clear and solid onset of solidification was observed after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: ' (M+H) + : 561. The NMIU map is provided in Figure 16. Yield: 0.27 g (79%).

'Ν'λ W To a solution of compound A (0.25 g, 0.60 mm 〇i) in acetonitrile (6 mL) was added diisopropylethylamine (0.42 mL, 2 4 decylpiperazine (0.1) mL, 0.90 mmol) and heating the reaction mixture to 8 (Γ.: heating, the reaction mixture became clear and solid precipitation began to be observed after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. 'Collected solids were washed with acetonitrile and dried in vacuo. LC/Ms: (M+H)+: 475. NMR spectrum is provided in Figure 17. Yield: 0.19 g (66%).

151808.doc •103- 201120037 To a solution of the compound hydrazine (0·25 g, 0.60 mmol) in acetonitrile (6 mL), diisopropylethylamine (0.42 mL, 2.4 mmol) Ethyl quinone 0 bottom ° (0·116 g, 0.90 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 503. The NMR spectrum is provided in Figure 18. Yield: 0'26 g (85%). Example 19

To a solution of the compound A (〇.25 g, 〇.6〇mm〇i) in acetonitrile (6 mL) was added diisopropylethylamine (0.42 mL, 24 〇1111 〇1) and 1 at room temperature. - Ethyl piperazine (0.12 mL, 0.94 mmol) and the reaction mixture was heated to 8 (rc.), the reaction mixture became clear upon heating and solid precipitation began to be observed after about 5 minutes. Heating was continued for 3 hours and then cooled. The reaction mixture was collected by suction <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI>

151808.doc -104- 201120037 Add diisopropylethylamine (0.42 mL, 2.4 mmol) to a solution of the compound Α (0·25 g, 0·60 mmol) in EtOAc (6 mL). And 1-isopropylpyrazine (0.117 g '〇·91 mmol) and the reaction mixture was heated to 8 (TC. The reaction mixture became clear on heating and solid precipitation began to be observed after about 5 minutes. Continue heating The reaction mixture was cooled for 3 hours, and the obtained solid was collected by suction, washed with EtOAc and dried in vacuo. LC/MS: (M+H)+: 303. NMR spectrum is provided in Figure 20. Yield: 0_19 g (62%). Example 21

To a solution of Compound A (0.25 g, 〇_60 mmol) in EtOAc (6 mL), diisopropylethylamine (eluent (42 mL, 2.4 mmol) and piperazine (0.079 g, 0.92 mmol) And heating the reaction mixture to 80 ° C. Upon heating, the reaction mixture became clear and a solid sag began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration and washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 461. The NMR spectrum is provided in Figure 21. Yield: 0.21 g (75%). Example 22

151808.doc •105· 201120037 Add diisopropylethylamine (〇42 mL, 2.4 mmol) and '&gt; to a solution of Compound A (0.25 g, 0.60 mmol) in acetonitrile (6 mL). The ratio was determined (0.065 g '〇.9〇mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 446. The NMR spectrum is provided in Figure 22. Yield: 0.21 g (77%). Example 23 9 ο. 〇

Add diisopropylethylamine (0.6 mL, 3.44 mmol) and 595 J (0.356 g) to a solution of Compound B ( 〇.2 g, 〇_54 mmol) in acetonitrile (5 mL). , 〇·75 mmol) and the reaction mixture was stirred at 80 ° C for 3 hours. Heating was then stopped and the reaction mixture was allowed to stand overnight, during which time a solid precipitate appeared. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 465. The NMR spectrum is provided in Figure 23. Yield: 0.18 g (72%). Example 24

151808.doc -106- 201120037 Add diisopropylethylamine (0.4 mL, 2.3 mmol) and 1-(2) to a solution of Compound B (0.2 g, 0.54 mmol) in EtOAc (5 mL) -pyridyl)piperazine (0.132 g, 0.81 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)' 498. The NMR spectrum is provided in Figure 24. Yield··0.21 g (78°/〇). Example 25

Add isopropylethylamine (〇_4 mL, 2.3 111111〇1) and 1-cyclohexylpiperazine to a solution of Compound B (0.2 g '0.54 mmol) in EtOAc (5 mL) 0.138 g '0.82 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 5 03. The NMR spectrum is provided in Figure 25. Yield: 0.2 g (74%). Example 26 151808.doc •107· 201120037

Add diisopropylethylamine (0.4 mL, 2.3 mmol) and 1-(4-trimethylphenyl) to a solution of compound B (0.2 g, 0.54 mmol) in EtOAc (5 mL) Piperazine (0.187 g, 0.81 mmol) and the reaction mixture was heated to 80 C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 565. The NMR spectrum is provided in Figure 26. Yield: 0.22 g (72%). Example 27

Add diisopropylethylamine (〇·4 mL, 2.3 mmol) and (R)-(-) to a solution of Compound B (〇2 g, 0.54 mmol) in acetonitrile (5 mL). -2-Methylpiperazine (0.081 g, 〇·81 mmol) and the reaction mixture was heated to 80 C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 1 $ minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 435. The NMR spectrum is provided in Figure 27. Yield: 0.13 g (55%). 151808.doc -108- 201120037 Example 28

To a solution of compound B (0.25 g, 0.67 mmol) in acetonitrile at room temperature was added monoisopropylethylamine (0.5 mL ' 2.9 mmol) and cis-2,6- dimethylpyrazine (0.115 § 1.11111111〇1) and heat the reaction mixture to 8〇. (: When heating, the reaction mixture became clear and solid precipitation began to be observed after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The obtained solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H) + : 449 ° NMR spectrum is provided in Figure 28. Yield · · 0.155 g (51%). Example 29

To the solution of the compound hydrazine (0·25 g '0.67 mmol) in acetonitrile (6 mL) in hexanes (0.5 mL, 2.9 mmol) and (R)-3- Monoamine pyridinidine (0.115 g, 1.01 mm 〇i) and the reaction mixture was heated to 80 ° C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 15 minutes. Heating was continued for 3 hours. The reaction mixture was then cooled. The obtained solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H) + : 449 NMR NMR NMR 201120037 Yield: 0.24 g (79%). Example 30

To a solution of the compound hydrazine (〇·25 g, 〇·67 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (5 mL, 2.9 mmol) and 2-methyl Bilo bites (0.086 g, 1.01 mmol) and the reaction mixture is heated to 8 Torr. Hey. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 420. The NMR plot is provided in Figure 30. Yield: 0.21 g (74%). Example 31

To a solution of compound B (0.25 g, 0.67 mmol) in acetonitrile (5 mL), diisopropylethylamine (5 mL, 2.9 mmol) and 4-(1-pyrrolidinyl) Piperidine (0.156 g, 1.01 mm 〇i) and the reaction mixture was heated to 8 °C. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo 151 808.doc. LC/MS: (M+H)+: 489. The NMR spectrum is provided in Figure 31. Yield: 0.23 g (70 ° / 〇). Example 32

MeO To a solution of the compound hydrazine (0.25 g, 0.67 mmol) in acetonitrile (5 mL), diisopropylethylamine (5 mL, 2.9 mmol) and (S)-2- (Methoxymethyl) ° bite (0.116 g, 1·mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 45 〇. The NMR spectrum is provided in Figure 32. Yield: 0.24 g (79 〇 / 〇). Example 33

Add diisopropylethylamine (0.5 mL, 2.9 mmol) and (R)-2-(methoxy oxime) to a solution of Compound B (0.25 g, 0-67 mmol) in EtOAc (5 mL) The reaction mixture became clear and the solid precipitate began to appear after about 15 minutes when the pyridinium (0.116 g, 1.0 mmol) was heated and the reaction mixture was heated to 8 ° C. Continue heating for 3 hours and then cool the reverse 151808.doc 201120037 to the mixture. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 450. The NMR spectrum is provided in Figure 33. Yield: 0.23 g (76 ° / 〇). H2n

Add Diisopropylethylamine (0.5 mL, 2.9 mmol) and (R)-3-Aminopyrrole to the solution of Compound B (0.25 g, 0.67 mmol) in acetonitrile (5 mL). Pyridine (0.087 g, 1.01 mmol) and the reaction mixture was heated to 8 〇〇c. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 421. The NMR spectrum is provided in Figure 34. Yield: 0.15 g (53 ° / 〇). Example 35

To the compound B (〇.25 g, 0.67 mm〇i) in acetonitrile (5 mL) was added diisopropylethylamine (〇5 mL, 2 9 and 3 pyrrole 11 decyl alcohol) 〇·_ g ' rtn mmGl) and heating the reaction mixture to the sail. The heated reaction mixture became clear and after about 5 minutes it was observed that 151808.doc •112-201120037 solid precipitate began to appear. Heating was continued for 3 hours and then The reaction mixture was cooled. The obtained solid was collected by EtOAc (EtOAc) eluted with EtOAc (EtOAc: EtOAc: EtOAc: Example 36

Add diisopropylethylamine (0.5 mL, 2-9 mmol) and 3-(diethylamino) to a solution of compound B (0.25 g, 0-67 mmol) in acetonitrile (5 mL). Biropyridine (0.144 g, 1.01 mmol) and the reaction mixture was heated to 80 °C. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H), 477. The NMR spectrum is provided in Figure 36. Yield: 0.25 g (78%). Example 37

Add diisopropylethylamine (0.5 mL, 2.9 mmol) and morpholine (0.088 g' l_〇i mmo) to a solution of Compound B (0.25 g, 0.67 mmol) in EtOAc (5 mL) 1) And heat the reaction mixture to 80 °C. On heating, 151808.doc -113- 201120037 The reaction mixture became clear and a solid sag began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration and washed with acetonitrile and dried in vacuo. LC/MS: 422. The NMR spectrum is provided in Figure 37, yield: 0.24 g (84%). Example 38

Add isopropylethylamine (〇5 mL, 2.9 mmol) and Ι-boc to the solution of Compound B (〇25 g, 〇67 mm〇1) in acetonitrile (5 mL) at rt. -0 bottom ° Qin (〇.189 吕, 1.〇1111111〇1) and the reaction mixture was heated to 8〇. (: When heating, the reaction mixture became clear and a solid sink began to be observed after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by the reaction, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 521. NMR spectrum is provided in Figure 38. Yield: 0.14 g (40%).

Add diisopropylethylamine (0.5 mL, 2.9 mmol) and 1-mercapto 151808.doc-114 to a solution of Compound B (25 g, 0.67 mmol) in EtOAc (5 mL) · 201120037 Piperazine (0.1 02 g '1.02 mmol) and heat the reaction mixture to 8 〇»c. Upon heating, the reaction mixture became clear and solid precipitation began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried <RTI ID=0.0># </RTI> <RTI ID=0.0> The NMR spectrum is provided in Figure 39. Yield: 0.125 g (43 ° /.). Example 40

To a solution of the compound B (0.25 g, 0.67 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (〇_5 mL, 2.9 mmol) and 1-ethylhydrazine piperazine (0.13) g, 1.01 mmol) and the reaction mixture was heated to 8 〇. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 463. The NMR spectrum is provided in Figure 4〇. Yield: 0.26 g (83%). Example 41

To a solution of Compound B (0.25 g, 〇·67 mm〇i) in acetonitrile (5 mL) 151808.doc -115· 201120037 was added diisopropylethylamine (0.5 mL, 2.9 mmol) at rt. 1-ethyloxazine (0.115 g, 1. oi mmol) and the reaction mixture was heated to 80. (: When heating, the reaction mixture became clear and solid precipitation began to be observed after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The obtained solid was collected by hydrazine, washed with acetonitrile and in vacuo. Dry. LC/MS: 449. NMR spectrum is provided in Figure 41. Yield: 0-22 g (73 ° / 〇). Example 42 9 〇.

Add diisopropylethylamine (0.5 mL, 2.9 mmol) and 1-isopropyl 0 bottom to the solution of the compound Β (0·25 g, 0.67 mmol) in acetonitrile (5 mL) at room temperature. Noise (0.13 g '1.01 mm〇l) and heat the reaction mixture to 8 Torr. Hey. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 5 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 463. The NMR spectrum is provided in Figure 42. Yield: 0.125 g (40 ° / 〇). Example 43

151808.doc 116- 201120037 Add isopropylethylamine (0.5 mL, 2.9 mmol) to the solution of Compound B (〇.25 g, 〇·67 mmol) in acetonitrile (5 mL). And limazine (0.087 g, i.01 mm 〇 1) and the reaction mixture was heated to 8 〇 &lt; t. Upon heating, the reaction mixture became clear and a solid precipitate began to appear after about 15 minutes. Heating was continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration and washed with acetonitrile and dried in vacuo. LC/MS: (M+H)+: 421. The NMR spectrum is provided in Figure 43. Yield: 0.21 g (74%). Example 44 ?\ «Ρ

Add diisopropylethylamine (〇 5 mL, 2 9 mm〇1) and pyrrolidine (0.072 g) to a solution of compound B (〇25 g, 0.67 mmol) in acetonitrile (5 mL). , l_〇i mm〇i) and the reaction mixture was heated to 8 Torr. Hey. Upon heating, the reaction mixture became clear and after about 15 minutes it was observed that the onset of solid/external heating continued for 3 hours and then the reaction mixture was cooled. The resulting solid was collected by filtration, washed with acetonitrile and dried in vacuo. lC/ms: (M+H)+: 406. The NMR spectrum is provided in Figure 44. Yield: 0.22 g (80%). The above-described embodiments of the present invention are intended to be illustrative only, and those skilled in the art will recognize or be able to determine many equivalents of particular compounds, materials, and procedures using routine experiment. All such equivalents are considered to be within the scope of the present invention, the disclosure of which is incorporated herein by reference. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 provides an NMR spectrum of the compound of Example 1. Figure 2 provides an NMR spectrum of the compound of Example 2. Figure 3 provides an NMR spectrum of the compound of Example 3. Figure 4 provides an NMR spectrum of the compound of Example 4. Figure 5 provides an NMR spectrum of the compound of Example 5. Figure 6 provides an NMR spectrum of the compound of Example 6. Figure 7 provides an NMR spectrum of the compound of Example 7. Figure 8 provides an NMR spectrum of the compound of Example 8. Figure 9 provides an NMR spectrum of the compound of Example 9. Figure 10 provides an NMR spectrum of the compound of Example 10. Figure Π provides an NMR spectrum of the compound of Example 11. Figure 12 provides an NMR spectrum of the compound of Example 12. Figure 13 provides an NMR spectrum of the compound of Example 13. Figure 14 provides an NMR spectrum of the compound of Example 14. Figure 15 provides an NMR spectrum of the compound of Example 15. Figure 16 provides an NMR spectrum of the compound of Example 16. Figure 17 provides an NMR spectrum of the compound of Example 17. Figure 18 provides an NMR spectrum of the compound of Example 18. Figure 19 provides an NMR spectrum of the compound of Example 19. Figure 20 provides an NMR spectrum of the compound of Example 20. Figure 21 provides an NMR spectrum of the compound of Example 21. Figure 22 provides an NMR spectrum of the compound of Example 22. 151808.doc • 118· 201120037 Figure 23 provides an NMR spectrum of the compound of Example 23. Figure 24 provides an NMR spectrum of the compound of Example 24. Figure 25 provides an NMR spectrum of the compound of Example 25. Figure 26 provides an NMR spectrum of the compound of Example 26. Figure 27 provides an NMR spectrum of the compound of Example 27. Figure 28 provides an NMR spectrum of the compound of Example 28. Figure 29 provides an NMR spectrum of the compound of Example 29. Figure 30 provides an NMR spectrum of the compound of Example 30. Figure 31 provides an NMR spectrum of the compound of Example 31. Figure 32 provides an NMR spectrum of the compound of Example 32. Figure 33 provides an NMR spectrum of the compound of Example 33. Figure 34 provides an NMR spectrum of the compound of Example 34. Figure 35 provides an NMR spectrum of the compound of Example 35. Figure 36 provides an NMR spectrum of the compound of Example 36. Figure 37 provides an NMR spectrum of the compound of Example 37. Figure 38 provides an NMR spectrum of the compound of Example 38. Figure 39 provides an NMR spectrum of the compound of Example 39. Figure 40 provides an NMR spectrum of the compound of Example 40. Figure 41 provides an NMR spectrum of the compound of Example 41. Figure 42 provides an NMR spectrum of the compound of Example 42. Figure 43 provides an NMR spectrum of the compound of Example 43. Figure 44 provides an NMR spectrum of the compound of Example 44. 151808.doc -119-

Claims (1)

201120037 VII. Scope of application for patents·· 1. A compound of formula I, (R6)m or a pharmaceutically acceptable salt thereof; wherein R is a phenyl group, a decyl group, a dentate group, a oxy group or a thiol group; and R and R together with a nitrogen atom substituted therewith form a substituted or An unsubstituted heterocyclic ring, wherein when a substituent is present, the substituents are selected from 1, 2 or 3 selected from the group consisting of an alkyl group, an amine group, an alkylamino group, an alkoxy group, a hydroxyl group, and a functional group. , _alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, haloalkylaryl, heterocyclyl, heteroaryl, alkoxyalkyl, alkylcarbonyl and alkoxycarbonyl The Q1 group; R4 and R5 are selected as follows: i) R4 and R5 are each an alkyl group, or ii) R4 and R5 together with the nitrogen atom substituted thereto form a substituted or unsubstituted heterocyclic ring in which a substituent is present When the substituents are selected from one or more Q2 groups selected from the group consisting of an alkyl group, an alkyl group, a chiral alkyl group, an alkoxy group and a transradical group; R6 is a halo group, a pyridyl group, a halo group, an alkoxy group. Or a radical; R7 is hydrogen, halo, thiol, fluorenyl, alkoxy or via. η is 0 to 2; m is 0 to 2; and 151808.doc 201120037 where Q1 is 1 , 2 or 3 selected from Group, substituted alkyl group, an amine group, an alkoxy group, a hydroxyl group, and the teeth of the group. 2. The compound of claim 1 wherein the sizing! is a halo or an alkyl group; R and R together with the nitrogen atom substituted thereto form a substituted or unsubstituted heterocyclic ring, wherein when a substituent is present, such The substituent is selected from 1, 2 or 3 selected from the group consisting of alkyl, amine, alkylamine, alkoxy, hydroxy, halo, dentate, cycloalkyl, aryl, arylalkyl , alkyl aryl, li alkyl aryl, heterocyclic, heteroaryl, alkoxyalkyl, alkylcarbonyl and alkoxycarbonyl β groups; R4 and R5 are selected as follows: i) R4 and R5 Is an alkyl group, ii) R4 and R5 together with a nitrogen atom substituted therewith form a substituted or unsubstituted 5 or 6 membered heterocyclic ring; wherein when a substituent is present, the substituents are selected from 1 or 2 a group selected from a group and an alkyl group; R6 is a halogen group or an alkyl group; R is hydrogen, a halogen group or a burnt group; η is 0 or 1; and m is ruthenium or 1. 3. The compound of claim 1 wherein R2 and R3 together with the nitrogen atom substituted therewith form a pyridyl, piperidinyl, piperazinyl or morpholinyl ring, wherein when a substituent is present, The substituent is selected from the group consisting of 丨, 2 or 3 selected from the group consisting of alkyl, amine, alkylamine, alkoxy, hydroxy, halo, haloalkyl, cycloalkyl, aryl, arylalkyl , alkylaryl, _alkylaryl, heterocyclyl, heteroaryl, alkoxyalkyl, alkylcarbonyl and alkoxycarbonyl 151808.doc -2 - 201120037 based on the Q1 group. 4. The compound of claim i, wherein the Q1 group is selected from the group consisting of methyl, ethyl, isopropyl, trifluoromethyl, amine, methylamino, diammonium, diethylaminooxyl Alkyl, anthracenyloxy, hydroxy, phenyl, trifluoromethylphenyl, cyclohexyl, piperidinyl, pyrrolidinyl, methylcarbonyl and tert-butoxy. 5. The compound of claim 1 wherein R4 and R5 are each a fluorenyl group. 6. The compound of claim 1 wherein the compound has the formula IA: Or a pharmaceutically acceptable salt thereof; wherein R and R3 together with the nitrogen atom substituted there form a pyrrolidinyl, piperidinyl, pyrazinyl or morpholinyl ring, wherein when a substituent is present, the substitution The base is selected from 1, 2 or 3 selected from the group consisting of alkyl, amine, alkylamine, alkoxy, hydroxy, dentyl, alkyl, cycloalkyl, aryl, arylalkyl, Alkylaryl, dentylaryl, heterocyclyl, heteroaryl, alkoxy, alkylcarbonyl and alkoxycarbonyl Q1 groups; and R4 and R5 are selected as follows: i) R4 and R5 An alkyl group; or hydrazine) R4 and R5 together with a nitrogen atom substituted therewith form an unsubstituted heterocyclic ring. The compound of any one of claims 1 to 6, wherein the compound has the formula 151808.doc 201120037 IB : 201120037 8. : Its pharmaceutically acceptable salt 'where? is 〇 to 3, q is. Or Chuan 9 :, an amine group, a mercaptoamine group, a thiol group, an alkoxy group or an alkoxy group. I. The compound of any one of item (1), wherein the compound has 3 (Q1)P R14 1C or a pharmaceutically acceptable salt thereof, wherein R&quot; is hydrogen, alkyl, dentyl, aryl, arylalkyl, alkylaryl, dentylaryl, alkylcarbonyl, cycloalkyl a aryl group, a heteroaryl group, a heterocyclic group or a pyridyl group; Q1 is a daunyl group; P is 〇, 1 or 2. The compound of any one of claims 1 to 6, wherein the compound has the formula IG : (Q IG or a pharmaceutically acceptable salt thereof, wherein p is 〇 to 3; Q! is an amino group, an alkyl group, a trans group, an alkoxy group or an alkoxy group; and R4 and R5 are each 151808. Doc -4- 201120037 Base. A compound of any one of items 1 to 6 wherein the compound has the formula IH: W m or a pharmaceutically acceptable salt thereof, wherein R 14 is hydrogen, decyl, ethyl, isopropyl, trifluoromethyl, phenyl, methylcarbonyl, cyclohexyl, trifluoromethyl strepyl, pyridine Or pyrrolidinyl, piperidinyl or tert-butoxycarbonyl; Q is methyl; p is 0, 1 or 2; R4 and R5 are each methyl. 11. A compound of formula II, 〇 〇 Or a pharmaceutically acceptable salt thereof; wherein R and R are each independently hydrogen, thiol, thiol, haloalkyl, methoxy or thiol; R8 and R9 together with a nitrogen atom substituted therewith a substituted or unsubstituted heterocyclic ring, wherein when a substituent is present, the substituent is selected from one or more selected from the group consisting of an alkyl group, an amine group, an alkylamino group, an alkoxy group, a hydroxyl group, a halogen group, Alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, haloalkylaryl, heterocyclyl, heteroaryl, alkoxyalkyl, alkylcarbonyl 151808.doc 201120037 and alkane a Q3 group of an oxycarbonyl group; R is a dentate group, an alkyl group, a dentate alkyl group, an alkoxy group or a hydroxy group; R13 is a hydroxy group or an alkoxy group; r is 0 to 2, and wherein Q3 is one or two as appropriate Or three groups selected from the group consisting of a halogen group, an alkyl group, an amine group, an alkoxy group, a hydroxyl group, and a valency group. 12. The compound of claim 11, wherein R10 and R11 are each independently hydrogen, halo or alkyl; R8 and R9 together with the nitrogen atom substituted therewith form a substituted or unsubstituted heterocyclic ring, wherein when present When substituted, the substituents are selected from one or more selected from the group consisting of alkyl, amine, alkylamino, alkoxy, hydroxy, i-, dentate, cycloalkyl, aryl, aryl a Q3 group of an alkyl group, an alkylaryl group, a halogenated aryl group, a heterocyclic group, a heteroaryl group, an alkoxyalkyl group, an alkylcarbonyl group, and an alkoxycarbonyl group; R12 is a halogen group or an alkyl group; R13 is a hydroxy or alkoxy group; and r is 0 or 1. 13. The compound of claim 12, wherein the substituted or unsubstituted 5 or 6 membered heterocyclic ring is formed together with the nitrogen atom substituted therewith, wherein when a substituent is present, the substituent is selected from the group consisting of 2 or 3 selected from alkyl, amine, alkylamino, alkoxy, hydroxy, i-, haloalkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkane a Q3 group of a aryl group, a heterocyclic group, a heteroaryl group, an alkoxyalkyl group, an alkylcarbonyl group, and an alkoxycarbonyl group. 151808.doc 201120037 14. The compound of claim 3, wherein R8 and R9 together with the nitrogen atom substituted there form a pyridyl, piperidinyl, piperazinyl or morpholinyl ring. 15. The compound of claim &quot;, wherein Rl0 and ruler 1 are each hydrogen. 16. A compound according to claim 1 or hydrazine, which is selected from the group consisting of: 7-((3S'4s)-3-methoxy-4-(methylamino)pyrrolidine-diyl)_3_(piperidine) Im_基基基基)-1-(thiazol-2-yl)-1,8-acridin-4(1 H)-one; 3_(piperidinylsulfonyl)_7_(4_(pyridine_2·yl) Piperazine_丨_yl)_丨_(thiazide-2-yl)-oxime, 8-acridin-4(1H)-one; 7-(4-cyclohexylpiperazin-1-yl)_3_ (l-pyridine-1-ylsulfonyl)_ι·(thiazol-2-yl)-1,8-acridine_4(1H)-one; 3-(pyridinium, hydrazine-ylsulfonyl)_丨_(thiazole_2•yl)·7 (4·(4_(trifluoromethyl)phenyl)piperazine-1-yl)-1,8-acridin-4(1Η)-one; (R)- 7-(3-Methylpiperazin-1-yl)-3-(piperidin-1-ylsulfonyl)_1_(thiazole-2-yl), 1,8-halide-4(1H)-嗣7兴(38,5汉)_3,5-Dimethylpiperazin-1-yl)-3-(piperidin-1-ylsulfonyl)-1-(thiazolyl-2-yl)-indole, 8·Acridine-4(1H)-one; (R)-7-(3-(Diammonium)pyrrolidin-1-yl)-3-(piperidin-1-ylsulfonyl)· 1 -(thiazole, 2-yl)-1,8-acridin-4(1H)-one; 7·(2·decylpyrrolidin-1-yl)-3-(piperidin-1-ylsulfonyl) )-1-(thiazol-2-yl)-1,8~嗉_4(lH)-_ ; 3-(娘啤酒-1_基牛牛)-7-(4-(&lt;1 ratio '1 each bite-1-yl) brigade bite-1-yl)-1- (sighs sit-2-base)_ι,8-peak bite-4(1H)-ketone; (S) -7-(2_(曱oxymethyl)** is 0-but-1-yl) -3-(Brigade. 1-1 ketone base) _1-(°-resazol-2-yl)-1,8-acridine·4(1Η)-ketone; 151808.doc 201120037 (R)-7 -(2-(methoxyindolyl)pyrrolidin-1-yl)-3-(piperidin-1-ylsulfonyl)-1-(thiazol-2-yl)-1,8-oxime Acridine-4(1H)-one; (R)-7-(3-amino.pyrrolidin-1-yl)-3-(piperidin-1-ylsulfonyl)-1-(thiazole-2 -yl)-1,8-acridin-4(1H)-one; 7 - (3 - thiol. piroxime-1 -yl)-3 - (派.定-1 - basement) - 1 - (sigh ° sitting -2_ base) -1,8-acridine-4(1H)-one; 7-(3-(diethylamino) π pirostole-1 -yl)-3-(. 。-1 -yl aryl-)-1 -(π- oxazol-2-yl)-1,8-acridin-4(1Η)-one; 7-(1^-morphinyl) (111 〇1卩11〇1111〇)-3-(0辰. 1,4-yl-based fluorenyl)-1-(°°°?2-yl)-1,8-acridin-4(1Η)-one; 4-(5-sideoxy(οχο)-6 -(piperidin-1-ylsulfonyl)-8-(thiazol-2-yl)-5,8-dihydro-1,8-acridin-2-yl)piperazine-1-carboxylic acid tert-butyl Ester; 7_(4 - 曱基旅°秦-1 -基)-3 - (派定定-1 - kiln)-1 - (β 塞σ坐-2 _ base)-1,8-喑Pyridin-4(1Η)-one; 7 - (4-ethoxylated α-endo-1 -yl)-3 - (slightly definite-1 -yl continuation)-1 - (α塞嗤-2 _ -1,8-acridin-4(1Η)-one; 7 - (4-ethylpyrazine-1 -yl)-3 - (Nymidine-1 -yl aryl)-1 -(嗟. sit -2_ base)-1,8-acridine-4(1Η)-one; 7_ (4-isopropyl group ° Qin-1 -yl)-3 - (Brigade σ定-1 - base continued brewing Base)-1 - (° stopper. sit-2-yl)-1,8-acridin-4(1Η)-one; 7-(piperazin-1-yl)-3-(piperidin-1-yl) Sulfhydryl)-1-(thiazol-2-yl)-1,8-acridin-4(1H)-one; 3-(Nymidine-1 -yl aryl)-7-(17 pirin °定-1 -yl)-1-(13⁄4 β sit-2-yl)-1,8_ acridine-4(1 Η)-one; 151808.doc 201120037 7-((3S,4S)-3-曱Oxy-4-(decyl)pyrrolidin-1-yldidecyl-4-yloxy-1-( Sesa-2 -yl)-1,4-dinitro-1,8-peak bite-3 - indeed amine; iV, iV~dimethyl-4-lateral gas group-7 -(4-(. Bite-2-yl)pyr-1-yl)-1 -(oxazol-2-yl)-1,4-dihydro-1,8-acridin-3-sulfonamide; 7-(4 -cyclohexylpiperazin-1-yl)-7V,7V-dimercapto-4-oxo-l-(thiazol-2-yl)-1,4-.mononitro-1,8-peak-beta -3 - arylamine, iv, iv-dimercapto-4-oxo-l-(thiazol-2-yl)-7-(4-(4-(trifluoromethyl)phenyl) Qin-1-yl)-1,4-dinitro-1,8-habit-3-strength amine, (R)-#,AT-dimethyl-7-(3-mercaptopiperazine-1 -yl)-4-oxo-l-(thiazol-2-yl)-1,4-dimur-1,8-peak bite-3 -continued amine, 7-((38,511)-3,5 -dimercaptopiperazin-1-yl)-#,#-dimercapto-4-yloxy-1 -(° stopper. sit-2-yl)-1,4-dinitro-1,8- 51 奈σ定-3 - continued amine, (R) -7-(3-(diamido)pyrrolidin-1-yl)-#, #-dimethyl-4-oxooxy-1 (° stopper-2-yl)-1,4 -diqi-1,8-peak °-3 - continued amine, dimercapto-7-(2-decylpyrrolidin-1-yl)- 4-sided oxy-1-(thiazol-2-yl)-1,4-dihydro-1,8-acridine-3-sulfonamide; 7V, dimethyl-4- -7- (4- (pyrrolidin-1-yl) piperidin-1-yl) -1- ([upsilon] plug. Sit 2,2-yl)-1,4-dinitro-1,8-peak bite-3-continued amine, (S)-7-(2-(methoxyindolyl).pyrrolidine-1- Dimercapto-4-yloxy-1 -(π塞°坐-2-yl)-1,4-dinitro-1,8-ρ-n-indene-3-continued amine, (R)- 7-(2-(Methoxyindenyl)pyrrolidin-1-yl)didecyl-4-yloxy-1 -(.sn-n-yl-2-yl)-1,4-di-rho-1 , 8 -11 Nabbit-3-Continuous amine, (R)-7-(3-Aminopyrrolidin-1-yldidecyl-4-yloxy-1-(thia 151808.doc 201120037 azole- 2-yl)-l,4-dihydro-1,8-acridin-3-sulfonamide; 7 - (3 -transpyridylpyrrolidine-1 -yl)-7V, iV-dimethyl -4 - flank-1 - (°°° sitting -2 · yl)-1,4 -diazo-1,8-p nap-3 - continuation of amine, 7-(3-(diethylamine) )) 比 ° ° -1- 基 基 基 ) ) ) -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 -4 Amine; dimercapto-7-(indolyl-morpholinyl)-4-yloxy-l-(thiazol-2-yl)-1,4-dihydro-1,8-acridin-3-sulfonate Amine; 4-(6-(7V,7V-didecylamine)--5-sideoxy-8 -(.septazin-2-yl)-5,8 ·diar-1,8- Acridine-2-yl)piperazine-1-carboxylic acid tert-butyl ester; 7V-two Base-7-(4-indolyl sigma-1 -yl)-4-sideoxy-1 - (° sigma -2 -yl)-1,4-di-r--1,8-peak. Ding-3 - continued amine, 7 · (4-ethylhydrazinopiperazin-1-yl)-7V, 7V-dimercapto-4-yloxy-1-(thiazol-2-yl)-1, 4 - di-rat-1,8-peak. Ding-3 - schistosamine, 7-(4-ethylpiperazin-1-yl)-7V, #·dimercapto-4-yloxy-1 ·(thiazol-2-yl)-1,4-diphos-1,8-peak.dine-3 -continued amine, 7-(4-isopropylpiperazin-1-yl)-#,#- Dimethyl-4.oxo-l-(thiazol-2-yl)-1,4-diaza-1,8-peak bite-3-continued amine, dimercapto-4-sideoxy- 7 ·(略17秦-1 -基)-1 - (σ塞ϋ sit-2 · base)-1,4_ two mice-1,8-peak °3 - indeed amine, 7V\7V·two Methyl-4-o-oxy-7-(°Biluo-1 -yl)-1 - (° plug. sit-2-yl)·1,4-dinitro-1,8-peak -3-Continuous amine, 3-((3S,4S)-3-decyloxy-4-(decylamino). Bilobidine-1-yl)-8-oxo-5-(thiazol-2-yl)-5,8-dihydropyrido[3,2-b]pyrazine-7-carboxylic acid; (S) -3-(3-(dimethylamino).pyrrolidin-1-yl)-8-sideoxy-5-(thiazole-2- 151808.doc -10- 201120037 base)-5,8-two Hydropyrido[3,2-b]pyrazine-7-decanoic acid; (S)-3-(3-amino-based D-Bylo-l-yl)-8-flank-5-(°塞 ° sit-2-yl)-5,8-dihydrogen. Ratio of [3, 2-1 &gt;] ° azine-7-decanoic acid; 3-(3-decyloxypyrrolidin-1-yl)-8-sideoxy-5-(thiazol-2-yl -5,8-dihydrogen 0 is more than 唆[3,2 - b ] ° ratio ° Qin-7-formic acid; 3-(3-hydroxy.pyrrolidin-1-yl)-8-sideoxy- 5-(thiazol-2-yl)-5,8-dihydropyrido[3,2-b]pyrazine-7-decanoic acid; 3 -(3-(diethylamino)°Pilo. 1 -yl)-8 - side-milk-5 - (°°° sitting -2 -yl)_ 5,8-dihydropyrido[3,2-b]pyrazine-7-carboxylic acid; 8 - side oxygen Base-3 - (α is 嘻. 定-1 -yl)-5 - (° plug. sit -2 - base) -5,8 - two mice. ratio. [3,2-b]pyrazine-7-carboxylic acid; 3-(2-methyl.pyrrolidin-1-yl)-8-sideoxy-5-(thiazol-2-yl)-5 , 8-dihydropyrido[3,2-b]pyrazine-7-decanoic acid; (R)-3-(2-(methoxymethyl).pyrrolidin-1-yl)-8- 5-oxy-5-(thiazol-2-yl)-5,8-dihydropyrido[3,2-b]pyrazine-7-carboxylic acid; (S)-3-(2-(methoxy)比)pyrrolidin-1-yl)-8-oxo-5-(thiazol-2-yl)-5,8-dihydropyrido[3,2-b]pyrazine-7-decanoic acid 3-(4-Methylpiperazin-1-yl)-8-oxo-5-(thiazol-2-yl)-5,8-dihydropyrido[3,2-b]pyrazine- 7-carboxylic acid; 3-(4-ethylpiperazin-1-yl)-8-oxo-5-(thiazol-2-yl)-5,8-dihydro. Bis-pyridyl[3,2-b]pyridazine-7-carboxylic acid; 3-(4-aryl-aryl-pyridyl-1 -yl)-8-sideoxy-5-(α塞.坐-2 - -5,8-diazapyrido[3,2-b]pyrazine-7-decanoic acid; 3-(4-cyclohexylpiperazin-1-yl)-8-oxo-5-( Thiazol-2-yl)-5,8-dihydro 151808.doc -11 - 201120037 Pyrido[3,2-b]. Bisylazine_7_carboxylic acid; 8·side oxy (anthracene) ten plugs. sitting 2_base)_5,8-dihydroindene and [3,2-b]pyrazine-7-decanoic acid; 3-((3S,5R)-3,5-dimethyl 0 base |, τ丞 guana-1-yl)·8_sideoxy_5_(thiazole_2_yl)-5,8-di Hydrogen pyrido[3,2讣]pyrazine, 7-formic acid; (R)-3-(3-indolyl 底 bottom. 奉-^ base) 8 phase Rong) 8 side gas group _5_(thiazole_2_ group )-5,8-dihydro-pyridylpyridinium[3,2-b]pyrazine-7-carboxylic acid; 8_sideoxy_5 sesaphthyl-2-yl)_3-(4-(4)(three 1 Methyl)phenyl)indolyl)-5,8-dihydropyrido[3,2_b]pyrazinic acid; 3-(4-isopropyl)•yl)_8_sideoxyna 2·yl)_58 diazolopyraz[3,2-b]pyrazine_7-carboxylic acid; morpholino)-8,oxy_5_(thiazole-2-yl)-5,8-dihydropyridinium[ 3,2-b]D-pyrazine-7-carboxylic acid; 8-sided oxy- 3- (4-(〇比 bit_2_其,us5·β主卜土)底秦-1-基)-5 -(thiazol-2-yl)-5,8-dihydro 0 is more than bite [3,2-b]. Bis-7-carboxylic acid; 8_sideoxy-3 - (4 - (. than ahha 1 y; \r (ratio 疋_1_yl) ° 啶 -1--1-yl)-5- (sold Zylo-2-yl)-5'8-dihydropyrido[3,2_b]pyrazine·7-carboxylic acid; and 3-(4-(tatabutoxy)pyrazine) $修坐-2-yl)_ 5,8-dihydropyrido[3,2_b]pyrazine_7-carboxylic acid. 17. A pharmaceutical composition, such as the compound of any one of items 1 to 16, and a pharmaceutically acceptable carrier. A method of treating cancer / which comprises administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 16. For example, the method of claim 18, wherein the cancer is bladder cancer, brain cancer, milk 151808.doc •12-201120037 cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal Cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer or hematological malignant disease. 20. The method of claim 18 or 19, further comprising administering a therapeutically effective agent to the second dose. 151808.doc -13-